Gamten, 100 mg/ml solution for infusion

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 <4g/l.

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

Measles pre-/post exposure prophylaxis for susceptible adults, children and adolescents (0-18 years) in whom active immunisation is contraindicated or not advised.

Consideration should also be given to official recommendations on intravenous human immunoglobulin use in measles pre-/post exposure prophylaxis and active immunisation.

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 polyradiculoneuropathy (CIDP)

• Multifocal motor neuropathy (MMN)

Immunomodulation in adults with:

• Active dermatomyositis treated with immunosuppressive drugs including corticosteroids, or with intolerance or contra-indications to those drugs

IVIg therapy should be initiated and monitored under the supervision of a physician experienced in the treatment of immune system disorders.

Posology

The dose and dose regimen are 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. In overweight patients dose should be based on the physiological standard bodyweight.

The following dosage regimens are given as guidance:

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. 3 – 6 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 every 3 – 4 weeks.

The dose required to achieve a trough level of 6 g/L is of the order of 0.2 - 0.8 g/kg/month.

The dosage interval when steady state has been reached varies from 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.

Replacement therapy in secondary immunodeficiencies (as defined in 4.1.)

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

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.

Measles pre-/post exposure prophylaxis

Post-exposure prophylaxis

If a susceptible patient has been exposed to measles, a dose of 0.4 g/kg given as soon as possible and within 6 days of exposure should provide a serum level > 240 mIU/mL of measles antibodies for at least 2 weeks. Serum levels should be checked after 2 weeks and documented. A further dose of 0.4 g/kg possibly to be repeated once after 2 weeks may be necessary to maintain the serum level > 240 mIU/ml.

If a PID/SID patient has been exposed to measles and regularly receives IVIg infusions, it should be considered to administer an extra dose of IVIg as soon as possible and within 6 days of exposure. A dose of 0.4 g/kg should provide a serum level > 240 mIU/ml of measles antibodies for at least 2 weeks.

Pre-exposure prophylaxis

If a PID/SID patient is at risk of future measles exposure and receives an IVIg maintenance dose of less than 0.53 g/kg every 3–4 weeks, this dose should be increased once to 0.53 g/kg. This should provide a serum level of >240 mIU/ml of measles antibodies for at least 22 days after infusion.

Immunomodulation in:

Primary immune thrombocytopenia

There are two alternative treatment schedules:

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

• 0.4 g/kg given daily for 2 – 5days. 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 polyradiculoneuropathy (CIDP):

Starting dose: 2g/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 physician's 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: 2g/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 physician's discretion based upon the patient's response and maintenance response. The dosing and intervals may have to be adapted according to the individual course of the disease.

Dermatomyositis (DM)

2g/kg given divided in equal doses over 2-5 consecutive days every 4 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 physician's discretion based upon the patient's response and maintenance response (see Section 5.1). The dosing and intervals may have to be adapted according to the individual course of the disease.

The dosage recommendations are summarised in the following table:

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 must be 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.

Gamten should be infused intravenously at an initial rate of 0.6 mL/kg/hr for 30 minutes. 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 7.2 mL/kg/hr.

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

Patients with dermatomyositis are considered patients at increased risk for thromboembolic events (see section 4.4) and should therefore be carefully monitored and infusion rate should not exceed 2.4 ml/kg/hr.

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

Hypersensitivity to the active substance (human immunoglobulins) or to any of the excipients (see Section 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.

This medicinal product contains 90 mg of maltose per ml as an excipient. The interference of maltose in blood glucose assays may result in falsely elevated glucose readings and, consequently, in the inappropriate administration of insulin, resulting in life threatening hypoglycaemia and death. Also, cases of true hypoglycaemia may go untreated if the hypoglycaemic state is masked by falsely elevated glucose readings (see Section 4.5). For acute renal failure see below.

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 human normal immunoglobulin by initially injecting the product slowly (0.6 to 1.2 mL/kg/hr);

• 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 a controlled healthcare setting in order to detect potential adverse signs and to ensure that emergency treatment can be administered immediately should problems occur. 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 IVIg infusion

• 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 infusion rate must be reduced or the infusion stopped. The treatment required depends on the nature and severity of the adverse reaction.

Infusion-related 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, dermatomyositis and a history of vascular disease or thrombotic episodes, patients with acquired or inherited thrombophilic disorders, patients with prolonged periods of immobilisation, severely hypovolemic patients, patients with diseases which increase blood viscosity).

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 at 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 not containing such excipients may be considered. Gamten contains maltose (see excipients above).

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 (CSF) 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 (RBC) with immunoglobulin, causing a positive direct antiglobulin reaction (Coombs' test) and, rarely, haemolysis. Haemolytic anaemia can develop subsequent to IVIg therapy due to enhanced RBC sequestration. IVIg recipients should be monitored for clinical signs and symptoms of haemolysis (see section 4.8).

Neutropenia/Leukopenia

A transient decrease in neutrophil count and/or episodes of neutropenia, sometimes severe, have been reported after treatment with IVIg. 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 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 HIV, HBV and HCV.

The measures taken may be of limited value against non-enveloped viruses such as HAV and parvovirus B19.

There is a reassuring clinical experience regarding the lack of hepatitis A or parvovirus B19 transmission with immunoglobulins and it is also assumed that the antibody content makes an important contribution to the viral safety.

Sodium content

This medicinal product contains 69 mg sodium per 100 ml, equivalent to 3.45% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

(Falsely) raised erythrocyte sedimentation rate

In patients who are receiving IVIg as a therapy, the erythrocyte sedimentation rate (ESR) may falsely be increased (noninflammatory rise).

Circulatory (volume) overload

Circulatory (volume) overload can occur when the volume of the infused IVIg (or any other blood or plasma-derived product) and other coincidental infusions cause acute hypervolaemia and acute pulmonary oedema.

Local injection site reactions:

Local reactions at the injection site have been identified which might include extravasation, infusion site erythema, infusion site pruritus, and similar symptoms.

Paediatric population

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

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.

Loop diuretics

Avoidance of concomitant use of loop diuretics

Blood Glucose Testing

Some types of blood glucose testing systems (for example, those based on the glucose dehydrogenase pyrroloquinolinequinone (GDH-PQQ) or glucose-dye-oxidoreductase methods) falsely interpret the maltose (90 mg/ml) contained in Gamten as glucose. This may result in falsely elevated glucose readings during an infusion and for a period of about 15 hours after the end of the infusion and, consequently, in the inappropriate administration of insulin, resulting in life-threatening or even fatal hypoglycemia. Also, cases of true hypoglycemia may go untreated if the hypoglycemic state is masked by falsely elevated glucose readings. Accordingly, when administering Gamten or other parenteral maltose- containing products, the measurement of blood glucose must be done with a glucose-specific method.

The product information of the blood glucose testing system, including that of the test strips, should be carefully reviewed to determine if the system is appropriate for use with maltose-containing parenteral products. If any uncertainty exists, contact the manufacturer of the testing system to determine if the system is appropriate for use with maltose- containing parenteral products.

Paediatric population

The listed interactions apply both to adults and children.

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. 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

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 breast-feeding mothers. 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.

Gamten has no or negligible influence on the ability to drive and use machines. However, patients who experience adverse reactions during treatment should wait for these to resolve before driving or operating machines.

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 Organ Class, adverse reactions are presented in order of decreasing seriousness.

Frequency of adverse drug reactions in clinical studies with Octagam:

The following reactions have been reported from post-marketing experience with Octagam

Frequencies for post-marketing reported reactions cannot be estimated from the available data.

Description of selected adverse reactions

For description of selected adverse events, such as hypersensitivity reactions, thromboembolism, acute renal failure, aseptic meningitis syndrome and haemolytic anaemia, see Section 4.4

Paediatric population

In clinical studies with Octagam most adverse reactions observed in children were graded as mild and many of them responded to simple measurements such as reduction of the infusion rate or temporary discontinuation of the infusion. With respect to the type of adverse reaction, all were recognised for IVIg preparations. The most frequent adverse reaction observed in the paediatric population was headache.

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 or search for MHRA Yellow Card in the Google Play or Apple App Store

Overdose may lead to fluid overload and hyperviscosity, particularly in patients at risk, including infants, elderly patients or patients with cardiac or renal impairment (see section 4.4).

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 donors. 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.

Clinical Studies

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

A total of 116 subjects were included in the analysis; 66 were subjects with chronic ITP, 49 were newly-diagnosed, and 1 subject was incorrectly enrolled in the study (had no ITP) and was therefore excluded from the efficacy analysis.

The overall response rate in the full analysis set was 80% (95% confidence interval: 73% to 87%). Clinical response rates were similar in the 2 cohorts: 82% in the chronic ITP cohort and 78% in the newly diagnosed cohort. In subjects with a response, the median time to platelet response was 2 days, with a range of 1 to 6 days.

The overall maximum infusion rate was 0.12 ml/kg/min. In the group of subjects in which a maximum infusion rate of 0.12 mL/kg/min was allowed (n=90), a median maximum infusion rate of 0.12 mL/kg/min (mean 0.10 mL/kg/min) was achieved. Overall, 55% of subjects experienced a drug-related adverse event, with a similar incidence in the chronic ITP and newly-diagnosed ITP cohort. All of the drug-related adverse events were mild or moderate in intensity, and all of them resolved. The most common adverse events were headache, increased heart rate (alterations in pulse rate of as little as > 10 beats/min were to be reported), and pyrexia. Drug-related infusional adverse events during or within 1 hour of infusions given at rates of ≤ 0.08 ml/kg/min occurred in 32 of 116 subjects (28%), while only 6 of 54 subjects (11%) had such adverse events at a rate of 0.12 ml/kg/min (if adverse event onset was after the end of the infusion, the last rate applied was assigned to the adverse event). There was no case of haemolysis related to the study drug. Pre-treatment to alleviate infusion-related intolerability was not given except in 1 subject.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP):

A retrospective study included data from 46 patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), who had been treated with Octagam 5%. The analysis of efficacy included 24 patients, with 11 untreated patients (group 1) and 13 patients who had received no immunoglobulins in the 12 weeks before the start of therapy with Octagam 5% (group 2). Group 3 contained 13 other patients who had been pretreated with immunoglobulins (immunoglobulins administered within 12 weeks before the start of administration of Octagam 5%). The treatment was regarded as effective if the ONLS (Overall Neuropathy Limitations Scale) was reduced by at least one point within 4 months of the start of treatment. In groups 1 and 2, the score was significantly reduced in 41.7% of the patients (p=0.02). Only 3 of the 13 patients (23.08%) in group 3 (pretreated with IVIg) exhibited an improvement in ONLS; 10 patients remained stable. No more marked improvement in the ONLS was to be expected for the patients pretreated with IVIg.

The mean age of the patients examined was 65 years, which is greater than in other CIDP studies. In patients older than 65 years, the response rate was lower than in younger patients. This is in accordance with published data.

Dermatomyositis (DM):

In a prospective, double-blind, randomized placebo-controlled, multicenter study a total of 95 adult patients (mean age 53 years, range 22-79 years, 75% female) with dermatomyositis were enrolled.

In the First Period (16 weeks), subjects received either 2 g/kg Gamten or placebo every 4 weeks for 4 infusion cycles.

Subjects could remain on their previous DM medication (maximum dosing, e.g. for corticosteroids: 20mg/day prednisone equivalent) if they were on stable dosing prior to enrolment. During the First Period concomitant DM medication dosing had to be kept stable and about 93% of subjects received corticosteroids (with appr. 50% receiving ≤10mg/day prednisone equivalent).

The proportion of responders (improvement of ≥20 points on the TIS) at week 16 in the Full Analysis Set (FAS) was significantly higher in the Gamten group than in the placebo group (78.72% versus 43.75%; Difference: 34.97% [95% CI: 16.70, 53.24; p=0.0008] see Table 1).

Table 1. Total Improvement Score –Proportion of Responders at Week 16

^aCochran-Mantel-Haenszel Test

'At least moderate improvement' defined as ≥40 points on the TIS and 'At least major improvement' defined as ≥60 points on the TIS, based on six Core Set Measures (CSM): Manual Muscle Testing MMT-8, Physician Global Disease Activity (GDA), Extramuscular Activity, Patient GDA, Health Assessment Questionnaire (HAQ), Muscle Enzymes.

CI=confidence interval; N=number of patients; TIS=total improvement score.

In the 24-week Open Label Extension (OLE) Period, 91 subjects went on to receive further 6 infusion cycles of Gamten every 4 weeks. Reduction of concomitant immunosuppressive treatment was permitted during this period and in 15% of subjects corticosteroid dosing could be tapered.

For all efficacy endpoints, through Week 40, the response in the Gamten group from the First Period was maintained. Subjects in the placebo group attained a similar response after switching to Gamten in the Extension Period (see Table 2).

Table 2 Total Improvement Score – Proportion of Responders at Week 40

A total of 664 infusion cycles with Gamten were administered during the entire study. Overall, 62 subjects (65.3%) experienced 282 treatment emergent adverse event that were considered related to study drug, the majority of which were mild in intensity (207/282). During the study no patient met the criteria for intravascular haemolysis.

During the study a reduction in the maximum allowed infusion rate from 0.12 mL/kg/min to 0.04 mL/kg/min was implemented. For both the placebo-controlled period and the entire study, exposure-adjusted incidence rates for thromboembolic events were consistently lower in the 'After reduction' analyses, (1.54 per 100 patient months before and 0.54 after reduction for the entire study). It is therefore recommended to use the lowest possible infusion rate in DM patients with risk factors (see also Section 4.4).

Paediatric population

No specific studies in the paediatric population were performed with Gamten.

However, a prospective open-label phase III study was performed with Octagam 5% in 17 children/adolescent patients (median age 14.0 years, range 10.5 to 16.8) suffering from primary immunodeficiency disorders. Patients were treated for a period of 6 months. The clinical efficacy was satisfying, as the number of days with infections or fever, and the number of days out of school were low, and the type and severity of infections was comparable to those observed in the normal population. No severe infections leading to hospitalisation were observed. It is also noteworthy that the number of infectious episodes was lower, when IgG plasma levels were maintained around 6 g/L than when the IgG plasma levels were around 4 g/L.

Absorption

Human normal immunoglobulin is immediately and completely bioavailable in the recipient's circulation after intravenous administration.

Distribution

It is distributed relatively rapidly between plasma and extravascular fluid, after approximately 3-5 days equilibrium is reached between the intra- and extravascular compartments.

Elimination

Human normal immunoglobulin has an average half-life ranging from 26 to 41 days, as measured in immunodeficient patients. This half-life may vary from patient to patient, in particular in primary immunodeficiency. For Gamten, no formal pharmacokinetic data in immunodeficient patients have been obtained.

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

Paediatric population

No specific studies in the paediatric population were performed with Gamten.

However, a prospective open-label phase III study was performed with Octagam 5% in 17 children/adolescent patients (median age 14.0 years, range 10.5 to 16.8) suffering from primary immunodeficiency disorders. Patients were treated for a period of 6 months.

During the treatment period, the average C_max in steady state was 11.1 ± 1.9 g/L; the average trough level was 6.2 ± 1.8 g/L. The terminal half-life of total IgG was 36 ± 11 days with a median of 34 days. The volume of distribution for the total IgG was 3.7 ± 1.4 L and the total body clearance was 0.07 ± 0.02 L/day.

Measles pre-/post exposure prophylaxis

No clinical studies have been performed in susceptible patients regarding Measles pre-/post exposure prophylaxis.

Gamten meets the minimum measles antibody potency specification threshold of 0.36x Center for Biologics Evaluation and Research (CBER) Standard. The dosing is based on pharmacokinetic calculations which take body weight, blood volume and half-life of immunoglobulins into consideration. These calculations predict a:

▪ Serum titer at 13.5 days = 270 mIU/mL (dose: 0.4 g/kg) This provides a safety margin more than double that of the WHO protective titer of 120 mIU/mL

▪ Serum titer at 22 days (t1/2) = 180 mIU/mL (dose: 0.4 g/kg)

▪ Serum titer at 22 days (t1/2) = 238.5 mIU/mL (dose: 0.53 g/kg –pre-exposure prophylaxis)

Immunoglobulins are normal constituents of the human body. Studies of repeated dose toxicity, genotoxicity, and toxicity to reproduction in animals are impracticable due to induction of and interference by developing antibodies to heterologous proteins. Since clinical experience provides no evidence for carcinogenic or mutagenic potential of immunoglobulins, no experimental studies in heterologous species were performed.

Maltose

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products, nor with any other IVIg products.

3 years

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

Store in a refrigerator (2°C – 8°C). Do not freeze.

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

The product may be removed from the refrigerator for a single period of up to 9 months (without exceeding the expiry date) and stored at a temperature ≤ 25°C. At the end of this period, the product should not be refrigerated again and should be disposed of. The date at which the product was taken out of the refrigerator should be recorded on the outer carton.

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

Pack sizes:

Not all pack sizes may be marketed.

20 ml of solution in a 30 ml vial.

50 ml of solution in a 70 ml bottle.

60 ml of solution in a 70 ml bottle.

100 ml of solution in a 100 ml bottle.

200 ml of solution in a 250 ml bottle.

300 ml of solution in a 300 ml bottle.

The vials/bottles are made of type II glass closed with bromobutyl rubber stoppers.

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

The solution should be clear to slightly opalescent and colourless or pale yellow.

Solutions that are cloudy or have deposits should be not used.

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