This information is intended for use by health professionals

1. Name of the medicinal product

Gamunex 10%,

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 98% IgG)

Each vial of 10 ml contains: 1 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

Each vial of 400 ml contains: 40 g of human normal immunoglobulin

Distribution of the IgG subclasses (approx. values):

IgG1 .................... 62.8%

IgG2 .................... 29.7%

IgG3 ...................... 4.8%

IgG4 ................…....2.7%

The maximum IgA content is 84 micrograms/ml.

Produced from the plasma of human donors.

For a full list of excipients, see section 6.1

This medicinal product contains less than 1 mmol sodium (23 mg) per single dose (up to a maximum of 2 g/kg), i.e. essentially 'sodium free'.

3. Pharmaceutical form

Solution for infusion

The solution is clear or slightly opalescent and colourless or pale yellow.

4. Clinical particulars
4.1 Therapeutic indications

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

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

• Secondary immunodeficiencies (SID) in patients who suffer from severe or recurrent infections, ineffective antimicrobial treatment and either proven specific antibody failure (PSAF)* or serum IgG level of <4 g/l.

*PSAF = failure to mount at least a 2-fold rise in IgG antibody titre to pneumococcal polysaccharide and polypeptide antigen vaccines

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 (in conjunction with acetylsalicylic acid; see 4.2)

• Chronic inflammatory demyelinating polyneuropathy (CIDP)

• Multifocal motor neuropathy (MMN)

Immunomodulation in adults aged ≥18 years in:

• Severe acute exacerbations of myasthenia gravis

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 dose regimen is dependent on the indication.

The dose may need to be individualised for each patient dependent on the clinical response. Dose based on bodyweight may require adjustment in underweight or overweight patients.

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 6 g/L or within the normal reference range for the population age. Three to six months are required after the initiation of therapy for equilibration (steady-state IgG levels) 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 IgG 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 3-4 weeks. IgG trough levels should be measured and assessed in conjunction with the incidence of infection. To reduce the rate of bacterial infections, it may be necessary to increase the dosage and aim for higher trough levels.

Secondary immunodeficiencies (as defined in 4.1)

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

IgG trough levels should be measured and assessed in conjunction with the incidence of infection. Dose should be adjusted as necessary to achieve optimal protection against infections, an increase may be necessary in patients with persisting infection; a dose decrease can be considered when the patient remains infection free.

Primary immune thrombocytopenia

There are two alternative treatment schedules:

• 0.8-1 g/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 (possible repeat of dosing in case of relapse).

Kawasaki disease

2.0 g/kg should be administered as a single dose. Patients should receive concomitant treatment with acetylsalicylic acid.

Chronic inflammatory demyelinating polyneuropathy (CIDP)

Starting dose: 2 g/kg divided over 2-5 consecutive days

Maintenance doses:

1 g/kg over 1-2 consecutive days every 3 weeks.

The treatment effect should be evaluated after each cycle; if no treatment effect is seen after 6 months, the treatment should be discontinued.

If the treatment is effective, long term treatment should be subject to the physicians discretion based upon the patient response and maintenance response. The dosing and intervals may have to be adapted according to the individual course of the disease.

Multifocal motor neuropathy (MMN)

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

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

The treatment effect should be evaluated after each cycle; if no treatment effect is seen after 6 months, the treatment should be discontinued.

If the treatment is effective long term treatment should be subject to the physicians discretion based upon the patient response and maintenance response. The dosing and intervals may have to be adapted according to the individual course of the disease.

Severe acute exacerbations of myasthenia gravis

2 g/kg divided over 2 consecutive days (dose of 1 g/kg per day).

Clinical studies of Gamunex 10% did not include sufficient numbers of subjects aged 65 and over to determine a precise treatment effect.

The dosage recommendations are summarised in the following table:

Indication

Dose

Frequency of injections

Replacement therapy

Primary immunodeficiency syndromes

Starting dose:

0.4 - 0.8 g/kg

Maintenance dose:

0.2 - 0.8 g/kg

 

every 3 - 4 weeks

Secondary immunodeficiencies (as defined in 4.1.)

0.2 - 0.4 g/kg

every 3 - 4 weeks

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

2 g/kg

in one dose in association with acetylsalicylic acid

Chronic inflammatory demyelinating polyneuropathy (CIDP)

Starting dose:

2 g/kg

Maintenance dose:

1 g/kg

 

in divided doses over 2-5 days

 

every 3 weeks over 1-2 days

Multifocal motor neuropathy (MMN)

Loading dose:

2 g/kg

Maintenance dose:

1 g/kg

or

2 g/kg

 

in divided doses over 2-5 consecutive days

 

every 2-4 weeks

or

every 4-8 weeks in divided doses over 2-5 days

Severe acute exacerbations of myasthenia gravis

2 g/kg

administered over 2 consecutive days

(dose of 1 g/kg per day)

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.

Hepatic impairment

No evidence is available to require a dose adjustment.

Renal impairment

No dose adjustment unless clinically warranted, see section 4.4.

Elderly

No dose adjustment unless clinically warranted, see section 4.4.

Method of administration

For intravenous use.

Human normal immunoglobulin should be infused intravenously at an initial rate of 0.6 – 1.2 ml/kg/hr for 0.5 hr. See section 4.4. In case of adverse reaction, either the rate of administration must be reduced or the infusion stopped. If well tolerated , the rate of administration may gradually be increased to a maximum of 4.8 – 8.4 ml/kg/hr.

4.3 Contraindications

Hypersensitivity to the active substance (human immunoglobulins) or to any of the excipients (see sections 4.4 and 6.1).

Patients with selective IgA deficiency who developed antibodies to IgA, as administering an IgA-containing product can result in anaphylaxis.

4.4 Special warnings and precautions for use

All patients should be closely monitored when high rates of infusion (8.4 ml/kg/hr) are used. In children or patients at risk of renal failure, the maximum infusion rate should not exceed 4.8 ml/kg/hr.

Gamunex 10% must not be mixed with other solutions for infusion (e.g. saline solution) and other medicinal products. If dilution is necessary prior to infusion, 50 mg/ml glucose solution may be used for this purpose. However, in case of latent diabetes (where transient glycosuria could appear), diabetes, or in patients on a low sugar diet use of a 50 mg/ml glucose solution should be carefully monitored. Also see warning about acute renal failure below.

Simultaneous administration of Gamunex 10% and heparin through a single lumen delivery device must be avoided.

Traceability

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

Precautions for use

Potential complications can often be avoided by ensuring that patients:

• are not sensitive to normal human immunoglobulin by initially injecting the product slowly (0.1 ml/kg/hr),

• are carefully monitored for any symptoms throughout the infusion period. In particular, patients naïve to human immunoglobulin, patients switched from an alternative IVIg product or when there has been a long interval since the previous infusion should be monitored at the hospital 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 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 (see 4.5).

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.

Infusion reaction

Certain adverse reactions (e.g. headache, flushing, chills, myalgia, wheezing, tachycardia, lower back pain, nausea and hypotension) 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.

Adverse reactions may occur more frequently

• 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

• in patients with an untreated infection or underlying chronic inflammation

Hypersensitivity

Hypersensitivity reactions are rare.

Anaphylaxis can develop in patients

• with undetectable IgA who have anti-IgA antibodies

• who had tolerated previous treatment with human normal immunoglobulin

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

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.

Renal parameters should be assessed prior to infusion of IVIG, particularly in patients judged to have a potential increased risk for developing acute renal failure and again to appropriate intervals. In patients at risk for acute renal failure, IVIg products should be administered at the minimum rate of infusion and dose practicable. In case of renal impairment, IVIg discontinuation should be considered.

While 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. Gamunex 10% does not contain sucrose, maltose or glucose.

Aseptic meningitis syndrome (AMS)

Aseptic meningitis syndrome has been reported to occur in association with IVIg treatment.

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.

Patients exhibiting such signs and symptoms should receive a thorough neurological examination, including CSF studies, to rule out other causes of meningitis.

Discontinuation of IVIg treatment has resulted in remission of AMS within several days without sequelae.

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).

The following risk factors are associated with the development of haemolysis: high doses, whether given as a single administration or divided over several days; non-0 blood group; and underlying inflammatory state. Increased vigilance is recommended for non-0 blood group patients receiving high doses for non-PID indications. Haemolysis has rarely been reported in patients given replacement therapy for PID.

Isolated cases of haemolysis-related renal dysfunction/renal failure with fatal outcome have occurred.

Neutropenia/Leukopenia

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.

Transfusion related acute lung injury (TRALI)

In patients receiving IVIg, there have been some reports of acute non-cardiogenic pulmonary oedema [Transfusion Related Acute Lung Injury (TRALI)]. TRALI is characterised by severe hypoxia, dyspnoea, tachypnoea, cyanosis, fever and hypotension. Symptoms of TRALI typically develop during or within 6 hours of a transfusion, often within 1-2 hours. Therefore, IVIg recipients must be monitored for and IVIg infusion must be immediately stopped in case of pulmonary adverse reactions. TRALI is a potentially life-threatening condition requiring immediate intensive-care-unit management.

Interference with serological testing

After the administration 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 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 human immunodeficiency Virus (HIV), hepatitis B Virus (HBV) and hepatitis C virus (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 that Gamunex 10% 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

Although limited data is available, it is expected that the same warnings, precautions and risk factors apply to the paediatric population. In post-marketing reports it is observed that IVIg high-dose indications in children, particularly Kawasaki disease, are associated with an increased reporting rate of haemolytic reactions compared to other IVIg indications in children.

Physicians need to strongly consider monitoring haemoglobin levels 24 to 48 hours after completion of IVIg if haemolysis is suspected. If retreatment is required it is strongly recommended to monitor haemoglobin levels one week after subsequent IVIg dosing if haemolysis is suspected. Families should be instructed to return if their child develops symptoms of haemolysis, such as; pallor, lethargy, dark urine, dyspnoea or palpitations.

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 or 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.

Loop diuretics

Avoidance of concomitant use of loop diuretics

Paediatric population

Although specific interaction studies have not been performed in the paediatric population, no differences between adults and children are to be expected.

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 expected.

Breast-feeding

Immunoglobulins are excreted into human milk. No negative effects on the breastfed newborns/infants are anticipated.

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 Gamunex 10%. 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 caused by human normal immunoglobulins (in decreasing frequency) encompass (see also Section 4.4):

• chills, headache, dizziness, fever, vomiting, allergic reactions, nausea, arthralgia, low blood pressure and moderate low back pain

• reversible haemolytic reactions; especially in those patients with blood groups A, B, and AB and (rarely) haemolytic anaemia requiring transfusion

• (rarely) a sudden fall in blood pressure and, in isolated cases, anaphylactic shock, even when the patient has shown no hypersensitivity to previous administration

• (rarely) transient cutaneous reactions (including cutaneous lupus erythematosus – frequency unknown)

• (very rarely) thromboembolic reactions such as myocardial infarction, stroke, pulmonary embolism, deep vein thromboses

• cases of reversible aseptic meningitis

• cases of increased serum creatinine level and/or occurrence of acute renal failure

• cases of Transfusion Related Acute Lung Injury (TRALI).

Tabulated list of adverse reactions

The table presented below is according to the MedDRA system organ classification (SOC and Preferred Term Level). Frequencies have been 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); not known (cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Source of the safety data base: clinical trials in a total of 703 patients exposed to Gamunex 10% (with a total of 4378 infusions)

MedDRA System Organ Class (SOC)

Adverse reaction

Frequency per patient

Frequency per infusion

Infections and infestations

Pharyngitis

Uncommon

Uncommon

Sinusitis, Urethritis, Viral upper respiratory tract infection

Uncommon

Rare

Blood and lymphatic system disorders

Haemolytic anaemia, Lymphocytosis

Uncommon

Rare

Immune system disorders

Hypersensitivity

Uncommon

Rare

Psychiatric disorders

Anxiety

Uncommon

Rare

Nervous system disorders

Headache

Very common

Common

Dizziness

Uncommon

Uncommon

Aphonia

Uncommon

Rare

Eye disorders

Photophobia

Uncommon

Rare

Vascular disorders

Hypertension

Common

Uncommon

Hypertensive crisis, Hypotension, Flushing, Hyperaemia

Uncommon

Rare

Respiratory, thoracic and mediastinal disorders

Wheezing, Cough, Nasal congestion,

Uncommon

Uncommon

Dyspnoea,

Uncommon

Rare

Gastrointestinal disorders

Nausea, Vomiting

Common

Uncommon

Abdominal pain, Diarrhoea, Dyspepsia

Uncommon

Rare

Skin and subcutaneous tissue disorders

Rash, Pruritus, Urticaria

Common

Uncommon

Skin exfoliation, Dermatitis, Contact dermatitis, Palmar erythema

Uncommon

Rare

Musculoskeletal and connective tissue disorders

Arthralgia, Back pain

Common

Uncommon

Myalgia

Uncommon

Uncommon

Musculoskeletal pain, Musculoskeletal stiffness, Neck pain

Uncommon

Rare

Renal and urinary disorders

Haemoglobinuria

Uncommon

Rare

General disorders and administration site conditions

Pyrexia

Common

Common

Influenza like illness, Chills, Fatigue

Common

Uncommon

Asthenia

Uncommon

Uncommon

Chest pain, Injection site reaction, Malaise

Uncommon

Rare

Investigations

Blood pressure increased, White blood cell count decreased, Haemoglobin decreased, Free haemoglobin present, Red blood cell sedimentation rate increased

Uncommon

Rare

Injury, poisoning and procedural complications

Contusion

Uncommon

Rare

Paediatric population

Frequency, type and severity of adverse reactions in children are expected to be the same as in adults.

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 via the national reporting system: Yellow Card Scheme; website: 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 (see section 4.4).

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 1,000 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.

Gamunex 10% is adjusted to a weakly acidic pH. Since Gamunex 10% has a low buffering capacity, it is rapidly neutralised by the blood during the infusion. Even after administration of high doses of Gamunex 10%, no change in the pH of the blood was recorded. Osmolality is 258 mOsmol/kg solution and thus approximates to the normal range (285-295 mOsmol/kg).

Clinical trials conducted with Gamunex 10% on patients with Chronic inflammatory demyelinating polyneuropathy (CIDP):

The IVIG-C CIDP efficacy trial (ICE study), a double-blind, randomised, placebo-controlled study investigated the efficacy and safety of Gamunex 10% in the treatment of CIDP. A total of 117 CIDP patients were randomised to receive either Gamunex 10% or placebo every three weeks. Loading dose was 2 g/kg BW; maintenance dose was 1 g/kg BW.

Responder rates (determined by improvement in INCAT disability score and maintenance of ≥ 1 improvement over the 24 week efficacy period) were significantly higher in the Gamunex 10% group (54%), compared to the placebo group (21%, p=0.0002). Muscle strength as measured by the MRC score and grip strength, as well as sensation as measured by the ISS score improved significantly more in the Gamunex 10% group compared to placebo.

In view of the limited number of patients ≥ 65 years included in the study, a precise treatment effect could not be determined with regard to the INCAT score; for grip strength, a statistically significant treatment effect was shown in favour of Gamunex 10%.

Of the responders, less than half responded after the loading dose (by week 3), but most responded after the second dose (by week 6). Non-responders were crossed over to the alternative treatment, for again up to a maximum of 24 weeks of therapy.

All responders were re-randomised in an extension phase for another 6 months period of maintenance therapy with either Gamunex 10% or placebo. Of the former responders to Gamunex 10%, the actual relapse rate was significantly higher in the patients randomised to placebo (42%) than in those randomised to Gamunex 10% (13%, p=0.012).

The ICE study has shown short-term and long-term efficacy of Gamunex 10% in the treatment of CIDP. The results are summarised in the following table.

Primary endpoint and other results of the ICE study

Gamunex 10%

Placebo

p

Responder rate during the efficacy period (primary endpoint)

54%

21%

0.0002

Probability of relapse in the extension period

13%

45%

0.013

Grip strength (kPA)1 (change from baseline)

Dominant hand

13.2

1.5

0.0008

Non-dominant hand

13.3

4.3

0.005

Muscle strength (MRC3 sum score)1 (change from baseline)

3.3

0.2

0.001

Sensibility (ISS4 score)2 (change from baseline)

-1.2

0.2

0.021

1 Improvement indicated by positive figure

2 Improvement indicated by negative figure

3 MRC: Medical Research Council

4 ISS: INCAT Sensory Sum Score

Clinical trials conducted with Gamunex 10% on patients with myasthenia gravis exacerbations:

The study by Zinman et al. (2007) was a randomised, double-blind, placebo-controlled study in 51 patients to evaluate Gamunex 10% 2 g/kg given over the course of 2 days in myasthenia gravis (MG) exacerbations. The primary efficacy endpoint was the change from baseline in QMG score on Day 14. On Day 14, the mean change in QMG score was -2.54 (p = 0.047). A clinically relevant effect on MG exacerbations was only observed in the exploratory subgroup of patients with moderate to severe MG at baseline (QMG score > 10.5), with a mean change of -3.39 (p = 0.010).

Additional support comes from a multicenter, prospective, open-label, non-controlled clinical trial, which also investigated the efficacy and safety of Gamunex 10% in the treatment of myasthenia gravis exacerbations. A total of 49 patients were enrolled into the clinical trial to receive a single, total dose of 2 g/kg of Gamunex 10% over 2 consecutive days (dose of 1 g/kg per day). There were no MuSK antibody positive patients who participated.

The primary efficacy endpoint was the change in Quantitative Myasthenia Gravis (QMG) score from baseline (day 0) to day 14. The mean changes in QMG score were -6.4 for the Evaluable and -6.7 for the Safety Population. Analysis of the secondary and exploratory efficacy endpoints results (assessed by QMG, MG-ADL, and MG Composite scores) supported the findings on the primary endpoint.

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.

Human normal immunoglobulin has a half-life of about 35 days as determined in patients with primary antibody deficiency syndrome and therefore exceeds that of 21 days described in the literature in healthy subjects. 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.

Paediatric population

No differences of the pharmacokinetic properties are expected in the paediatric population.

5.3 Preclinical safety data

Immunoglobulins are normal components of the human body. Because administration of immunoglobulins in animal studies may lead to the formation of antibodies, preclinical safety data are limited. In the acute and sub-acute animal studies that were performed, Gamunex 10% did not show special risks for humans.

6. Pharmaceutical particulars
6.1 List of excipients

Glycine, water for injection.

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf life

3 years

6.4 Special precautions for storage

Store at +2 °C to +8 °C (in a refrigerator). Do not freeze. Keep in outer carton.

The product may be stored in its outer carton for a one-off period of up to 6 months at room temperature (not above 25°C). In that case, the shelf life of the product expires at the end of this 6-month period. The new expiry date must be noted on the outer carton. The new expiry date must be no later than the printed expiry date. Thereafter, it must be used or destroyed. Subsequent refrigeration or freezing is not possible.

6.5 Nature and contents of container

Solution for intravenous infusion in Type I or II glass vials with chlorobutyl stoppers.

Pack sizes:

One vial of 10 ml contains: 1 g of human normal immunoglobulin

One vial of 50 ml contains: 5 g of human normal immunoglobulin

One vial of 100 ml contains: 10 g of human normal immunoglobulin

One vial of 200 ml contains: 20 g of human normal immunoglobulin

One vial of 400 ml contains: 40 g of human normal immunoglobulin

Not all pack sizes may be marketed.

6.6 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 and colourless or pale yellow. Solutions that are cloudy or have deposits should not be used.

Any unused product or waste material should be disposed of in accordance with local requirement. Once the container has been opened, the contents should be infused immediately. Subsequent storage, even in a refrigerator, is not permitted on account of possible microbial colonisation.

If dilution is necessary prior to infusion, 50 mg/ml glucose solution may be used for this purpose. Do not dilute with saline solutions.

Simultaneous administration of Gamunex 10% and heparin through a single lumen delivery device must be avoided.

Infusion lines can be flushed with 50 mg/ml glucose or with sodium chloride solution (9 mg/ml) and should not be flushed with heparin.

Heparin Lock through which Gamunex 10% was administered should be flushed with 50 mg/ml glucose or sodium chloride solution (9 mg/ml) and should not be flushed with heparin.

7. Marketing authorisation holder

Grifols Deutschland GmbH

Colmarer Straße 22

60528 Frankfurt

Germany

Tel.: +49 69-660 593 100

8. Marketing authorisation number(s)

PL 29527/0001

9. Date of first authorisation/renewal of the authorisation

Date of the first authorisation: 27.07.2006

Date of last renewal: 10.05.2011

10. Date of revision of the text

02/2020

Instructions for use of the vials (50 ml, 100 ml , 200 ml and 400 ml vials only)

The vials are supplied with a hanger label (Fig. 1). After inserting the infusion set (Fig. 2), invert the vial and fold back the loop section of the label (Fig. 3). Use firm finger pressure to create a crease on each side where the loop section joins the rest of the label (Fig. 4). Suspend the vial from the infusion stand by the resulting loop (Fig. 5).