This information is intended for use by health professionals

  This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1. Name of the medicinal product

IQYMUNE 100 mg/mL, solution for infusion

2. Qualitative and quantitative composition

Human normal immunoglobulin (IVIg)

One mL contains:

Human normal immunoglobulin…………………………………………100 mg

(Purity of at least 95 % IgG)

Each vial of 20 mL contains: 2 g of human normal immunoglobulin.

Each vial of 50 mL contains: 5 g of human normal immunoglobulin.

Each vial of 100 mL contains: 10 g of human normal immunoglobulin.

Each vial of 200 mL contains: 20 g of human normal immunoglobulin.

Distribution of the IgG subclasses (approx. values):

IgG1…………60 – 70 %

IgG2…………30 – 35 %

IgG3…………2 %

IgG4…………1 – 2 %

The maximum IgA content is 28 micrograms/mL.

Produced from the plasma of human donors.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Solution for infusion.

The solution is clear or slightly opalescent, colourless to pale brown.

4. Clinical particulars
4.1 Therapeutic indications

Replacement therapy in adults, and children and adolescents (0 – 18 years) in:

• Primary immunodeficiency (PID) syndromes with impaired antibody production (see section 4.4).

• Hypogammaglobulinaemia and recurrent bacterial infections in patients with chronic lymphocytic leukaemia, in whom prophylactic antibiotics have failed.

• Hypogammaglobulinaemia and recurrent bacterial infections in plateau phase multiple myeloma patients who have failed to respond to pneumococcal immunisation.

• Hypogammaglobulinaemia in patients after allogeneic haematopoietic stem cell transplantation (HSCT).

• Congenital AIDS with recurrent bacterial infections.

Immunomodulation in adults, and children and adolescents (0 – 18 years) in:

• Primary immune thrombocytopenia (ITP), in patients at high risk of bleeding or prior to surgery to correct the platelet count.

• Guillain Barré syndrome.

• Kawasaki disease.

• Multifocal motor neuropathy (MMN).

4.2 Posology and method of administration

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

Posology

The dose and dosage regimen are dependent on the indication.

In replacement therapy the dose may need to be individualised for each patient dependent on the pharmacokinetic and clinical response. The following dose regimens are given as a guideline.

Replacement therapy in primary immunodeficiency syndromes

The dose regimen should achieve a trough level of IgG (measured before the next infusion) of at least 5 to 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 given once, followed by at least 0.2 g/kg given every three to four weeks.

The dose required to achieve a trough level of 5 – 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 3 – 4 weeks.

Trough levels should be measured and assessed in conjunction with the incidence of infection. To reduce the rate of infection, it may be necessary to increase the dosage and aim for higher trough levels.

Hypogammaglobulinaemia and recurrent bacterial infections in patients with chronic lymphocytic leukaemia, in whom prophylactic antibiotics have failed; hypogammaglobulinaemia and recurrent bacterial infections in plateau phase multiple myeloma patients who have failed to respond to pneumococcal immunisation; congenital AIDS with recurrent bacterial infections

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

Hypogammaglobulinaemia in patients after allogeneic haematopoietic stem cell transplantation

The recommended dose is 0.2 – 0.4 g/kg every three to four weeks. The trough levels should be maintained above 5 g/L.

Primary immune thrombocytopenia

There are two alternative treatment schedules:

• 0.8 – 1g/kg given on day one; this dose may be repeated once within 3 days

• 0.4 g/kg given daily for two to five days.

The treatment can be repeated if relapse occurs.

Guillain Barré syndrome

0.4 g/kg/day over 5 days.

Kawasaki Disease

1.6 – 2.0 g/kg should be administered in divided doses over two to five days or 2.0 g/kg as a single dose. Patients should receive concomitant treatment with acetylsalicylic acid.

Multifocal Motor Neuropathy (MMN)

Starting dose: 2 g/kg given over 2-5 days.

Maintenance dose: 1 g/kg every 2 to 4 weeks or 2 g/kg every 4 to 8 weeks.

The dosage recommendations are summarised in the following table:

Indication

Dose

Frequency of infusions

Replacement therapy in primary immunodeficiency

- starting dose:

0.4 – 0.8 g/kg

- thereafter:

0.2 – 0.8 g/kg

every 3 – 4 weeks to obtain IgG trough level of at least 5 – 6 g/L

Replacement therapy in secondary immunodeficiency

0.2 – 0.4 g/kg

every 3 – 4 weeks to obtain IgG trough level of at least 5 – 6 g/L

Congenital AIDS

0.2 – 0.4 g/kg

every 3 – 4 weeks

Hypogammaglobulinaemia (< 4 g/L) in patients after allogeneic haematopoietic stem cell transplantation

0.2 – 0.4 g/kg

every 3 – 4 weeks to obtain IgG trough level above 5 g/L.

Immunomodulation:

Primary immune thrombocytopenia

0.8 – 1 g/kg

or

0.4 g/kg/d

on day 1, possibly repeated once within 3 days

for 2 – 5 days

Guillain Barré syndrome

0.4 g /kg/d

for 5 days

Kawasaki disease

1.6 – 2 g/kg

or

in divided doses over 2 – 5 days in association with acetylsalicylic acid

2 g/kg

in one dose in association with acetylsalicylic acid

Multifocal Motor Neuropathy (MMN)

starting

dose: 2 g/kg

maintenance

dose: 1 g/kg

or

2 g/kg

 

given over 2-5 days

every 2- 4 weeks

or

every 4 - 8 weeks

Paediatric population

The posology in children and adolescents (0 – 18 years) is not different to that of adults as the posology for each indication is given by body weight and adjusted to the clinical outcome of the above mentioned conditions.

Method of administration

For intravenous use.

Human normal immunoglobulin should be infused intravenously at an initial rate of 0.5 mL/kg/hr for 30 minutes. If well tolerated (see section 4.4), the rate of administration may gradually be increased to a maximum of 6 mL/kg/hr. Clinical data obtained from a limited number of patients with PID and ITP also indicate that adult and children patients may tolerate an infusion rate of up to 8 mL/kg/hr.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients (see section 6.1). Hypersensitivity to human immunoglobulins, especially in patients with antibodies against IgA.

4.4 Special warnings and precautions for use

Certain severe adverse reactions may be related to the rate of infusion. The recommended infusion rate given under section 4.2 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 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.

Potential complications can often be avoided by ensuring that patients:

• are not sensitive to human normal immunoglobulin by initially injecting the product slowly (0,5 mL/kg/h);

• 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.

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 adverse reaction.

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

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.

Hypersensitivity

True hypersensitivity reactions are rare. They can occur in patients with anti-IgA antibodies.

IVIg is not indicated in patients with selective IgA deficiency where the IgA deficiency is the only abnormality of concern.

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.

Thromboembolism

There is clinical evidence of an association between IVIg administration and thromboembolic events such as myocardial infarction, cerebral vascular accident (including 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 hypovolaemic patients, patients with diseases which increase blood viscosity).

In patients at risk for thromboembolic adverse reactions, IVIg products should be administered at the minimum rate of infusion and dose practicable.

Acute renal failure

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, hypovolaemia, 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 that do not contain these excipients may be considered. IQYMUNE does not contain sucrose, maltose nor glucose.

In patients at risk for acute renal failure, IVIg products should be administered at the minimum rate of infusion and dose practicable.

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially “sodium-free”.

Aseptic meningitis syndrome (AMS)

Aseptic meningitis syndrome has been reported to occur in association with IVIg treatment. Discontinuation of IVIg treatment has resulted in remission of AMS within several days without sequelae. The syndrome usually begins within several hours to 2 days following IVIg treatment. Cerebrospinal fluid studies are frequently positive with pleocytosis up to several thousand cells per mm3, predominantly from the granulocytic series, and elevated protein levels up to several hundred mg/dL.

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

Haemolytic anaemia

IVIg products can contain blood group antibodies which may act as haemolysins and induce in vivo coating of red blood cells with immunoglobulin, causing a positive direct antiglobulin reaction (Coombs' test) and, rarely, haemolysis. Haemolytic anaemia can develop subsequent to IVIg therapy due to enhanced red blood cells (RBC) sequestration. IVIg recipients should be monitored for clinical signs and symptoms of haemolysis. (See section 4.8.)

Neutrophil count decrease

A transient decrease in neutrophil count and/or episodes of neutropenia, sometimes severe, have been reported after treatment with IVIgs. This typically occurs within hours or days after IVIg administration and resolves spontaneously within 7 to 14 days. In IQYMUNE studies, this was not associated with an increased risk of infections in particular in patients with primary immunodeficiency.

The potential occurrence of neutrophil count decrease and/or neutropenia should be taken into account when administering IQYMUNE in patients with neutropenia or at risk of developing neutropenia such as those with chronic lymphocytic leukaemia or multiple myeloma or treated with cytotoxic chemotherapy.

Interference with serological testing

After infusion of immunoglobulin the transitory rise of the various passively transferred antibodies in the patient's 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 for red cell antibodies for example the direct antiglobulin test (DAT, direct Coombs' test).

Transmissible agents

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 infectious 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, and for the non-enveloped viruses 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 IQYMUNE 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.

Paediatric population

The listed warnings and precautions apply both to adults and children.

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 weeks and up to 3 months the efficacy of live attenuated virus vaccines such as measles, rubella, mumps and varicella. After administration of this medicinal 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.

Paediatric population

The listed interactions apply both to adults and children.

4.6 Fertility, pregnancy and lactation

Pregnancy

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. IVIg products have been shown to cross the placenta, increasingly during the third trimester. 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.

Breast-feeding

Immunoglobulins are excreted into the milk and may contribute to protecting the neonate from pathogens which have a mucosal portal of entry.

Fertility

Clinical experience with immunoglobulins suggests that no harmful effects on fertility are to be expected.

4.7 Effects on ability to drive and use machines

The ability to drive and operate machines may be impaired by some adverse reactions associated with IQYMUNE. Patients who experience adverse reactions during treatment should wait for these to resolve before driving or operating machines.

4.8 Undesirable effects

Summary of the safety profile

Adverse reactions such as chills, headache, dizziness, fever, vomiting, allergic reactions, nausea, arthralgia, low blood pressure and moderate low 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 and rare cases of transient cutaneous reactions have been observed with human normal immunoglobulin. Reversible haemolytic reactions have been observed in patients, especially those with blood groups A, B, and AB. Rarely, haemolytic anaemia requiring transfusion may develop after high dose IVIg treatment (see also Section 4.4).

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.

For safety information with respect to transmissible agents see section 4.4.

Tabulated list of adverse reactions

Three clinical studies were performed with IQYMUNE in Europe:

• one clinical study in 62 PID patients (36 adults and 26 children and adolescents) treated up to 12 months every 3 – 4 weeks. Doses were individually adjusted throughout the study to reach a target IgG trough level > 6g/L.

• one clinical study in 38 adult ITP patients treated at the standard recommended dose of 1 g/kg/day for two consecutive days.

• one clinical study in 22 adult patients in the maintenance phase of their MMN therapy. Patients were treated at 1 to 2 g/kg every 4 to 8 weeks, for about 24 weeks.

In total, 122 patients were exposed to 1105 infusions of IQYMUNE.

Almost all observed Adverse Reactions (ARs) were mild to moderate in intensity.

The table presented below follows the MedDRA system organ classification (SOC) and Preferred Term Level.

Frequencies were evaluated according to the following convention: 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).

Frequency of Adverse Drug Reactions (ADRs) reported during clinical trials with IQYMUNE.

MedDRA System Organ Class (SOC)

Adverse reaction

Frequency per infusion

(N = 1105 infusions)

Blood and lymphatic system disorders

Neutropenia

common

Leukopenia

Lymphopenia

Monocytopenia

uncommon

Immune system disorders

Anaphylactoid reaction

rare

Nervous system disorders

Headache

common

Dizziness

uncommon

Meningitis aseptic

rare

Ear and labyrinth disorders

Vertigo

rare

Vascular disorders

Hypertension

uncommon

Peripheral vascular disorder

rare

Gastrointestinal disorders

Nausea

Vomiting

Abdominal pain

uncommon

Oral pain

rare

Skin and subcutaneous tissue disorders

Rash

Pruritus

uncommon

Hyperhidrosis

Pain of skin

rare

Musculoskeletal and connective tissue disorders

Back pain

Arthralgia

Pain in extremity

Myalgia

uncommon

Bone pain

Musculoskeletal chest pain

Muscle spasms

rare

General disorders and administration site conditions

Pyrexia

Fatigue

common

Malaise

Influenza like illness

Oedema peripheral

Chills

uncommon

Feeling cold

Catheter site pain

rare

Investigations

Creatinine renal clearance decreased

Body temperature increased

Blood pressure increased

uncommon

Blood creatinine increased

rare

Injury, poisoning and procedural complications

Infusion related reaction

rare

Respiratory, thoracic and mediastinal disorders

Dry throat

rare

Paediatric population

In the PID study the frequency, nature and severity of adverse reactions did not differ between the 26 paediatric patients (≥ 24 months old) and the 36 adult patients.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important.

It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.mhra.gov.uk/yellowcard.

4.9 Overdose

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

5. Pharmacological properties
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 immunoglobulin G subclasses closely proportional to that in native human plasma. Adequate doses of this medicinal product may restore abnormally low immunoglobulin G levels to the normal range.

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

The efficacy of IQYMUNE as replacement therapy was evaluated in a total of 62 PID patients (36 adults and 26 paediatrics) including 4 naïve patients

The efficacy of IQYMUNE in immunomodulation was evaluated in 38 adult patients with chronic primary ITP with a platelet count < 30 x 109/L and in 22 adult patients with MMN.

Paediatric population

The European Medicines Agency has waived the obligation to perform clinical studies with IQYMUNE

• in all subsets of the paediatric population in ITP.

• in the paediatric population from birth to less than 24 months of age in PID.

• in all subsets of the paediatric population in MMN.

See 4.2 for information on paediatric use.

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 extravascular fluid, after approximately 3 – 5 days equilibrium is reached between the intra- and extravascular compartments.

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

Pharmacokinetic (PK) analyses of IQYMUNE were performed in the PID study in 28 stabilised adult patients. A population PK modelling was used as the primary PK analysis. The mean half-life of IQYMUNE is 33.6 days.

This half-life may vary from patient to patient, in particular in primary immunodeficiency.

Paediatric population

No pharmacokinetic analysis was performed with IQYMUNE in paediatric patients. However, trough levels observed in the 26 PID paediatric patients ≥ 24 months old were comparable to those obtained in PID adult patients.

5.3 Preclinical safety data

Immunoglobulin are normal constituent of the human body.

The safety of IQYMUNE has been documented in several non clinical studies. Non-clinical data revealed no toxicological effects (single dose toxicity in rats, local tolerance study in rabbits).

Repeated dose toxicity, genotoxicity, and reproductive toxicity studies in animals are impracticable due to induction of an interference by developing antibodies to heterologous proteins.

Since immunoglobulins are human proteins with no evidence of carcinogenic potential, no specific preclinical studies were performed.

6. Pharmaceutical particulars
6.1 List of excipients

Glycine

Polysorbate 80

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

36 months.

Once opened : use immediately.

6.4 Special precautions for storage

Do not store above 25°C.

Do not freeze.

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

For storage conditions after opening the medicinal product, see section 6.3.

6.5 Nature and contents of container

20, 50, 100, 200 mL of solution in a vial (Type I glass) with a stopper (elastomer), a cap (aluminium) and a flip off disc (polypropylene).

Pack size of one vial.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

The product should be at room or body temperature before use.

The solution should be clear or slightly opalescent, colourless to pale brown. Solutions that are cloudy or have deposits should not be used.

Once the container has been entered under aseptic conditions, its content should be used promptly. Because the solution contains no preservative, IQYMUNE should be infused as soon as possible and for a single use only.

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

7. Marketing authorisation holder

Laboratoire Français du Fractionnement et des Biotechnologies

3 Avenue des Tropiques

ZA de Courtaboeuf

91940 LES ULIS

FRANCE

Tel: + 33(0) 1 69 82 70 10

Fax: + 33(0) 1 69 82 19 03

8. Marketing authorisation number(s)

PL 17469/0007

9. Date of first authorisation/renewal of the authorisation

08.03.2016

10. Date of revision of the text

05.2018