CMDh/223/2005 February 2014

Public Assessment Report

Scientific discussion

Nanogam 100 mg/ml Human normal immunoglobulin

FI/H/0357/002/DC

Date: 26.2.2018

This module reflects the scientific discussion for the approval of Nanogam 100 mg/ml. The procedure was finalised at 3.10.2016 (Day 185). For information on changes after this date please refer to the module ‘Update’.

I. INTRODUCTION

Based on the review of the quality, safety and efficacy data, the Member States have granted a marketing authorisation for Nanogam 100 mg/ml solution for infusion, from Sanquin Plasma Products, Amsterdam, The Netherlands.

Nanogam 100 mg/ml is classified in the following pharmacotherapeutic group: immunosera and immunoglobulins; normal human immunoglobulin for intravascular administration, ATC code, J06BA02.

The product is indicated for:

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

• Primary immunodeficiency 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.

A comprehensive description of the indications and posology is given in the SmPC.

The marketing authorisation has been granted pursuant to Article of Directive 2001/83/EC.

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II. QUALITY ASPECTS

II.1 Introduction

Nanogam, 100 mg/ml, solution for infusion, is a human normal immunoglobulin for intravenous administration (IVIg) presented in liquid form. It is prepared from human plasma and contains mainly IgG. Nanogam contains glucose monohydrate and water for injections as excipients. Glass vials of Ph. Eur. glass type II are used for the product for all package sizes with filling volumes 10 ml, 25 ml, 50 ml, 100 ml, 200 ml and 300 ml.

II.2 Drug Substance

The active substance for Nanogam 100 mg/ml is human normal immunoglobulin which fulfils the requirements set in Ph.Eur. monograph 0918. It is obtained from human plasma that is in compliance with Ph.Eur. monograph 853. Plasma is EMA certified; Sanquin PMF (certificate no. EMEA/H/PMF/000007/04/#/#), Sanquin US plasma PMF (certificate no EMEA/H/PMF/00017/14/# #), CAF-DCF PMF (certificate no. EMEA/H/PMF/000010/06/#/#), Biotest PMF (certificate no. EMEA/H/PMF/000009/05/#/#). Purification of IgG from plasma pool is performed by the modified Cohn fractionation process. The manufacturing process (including in-process testing) from human plasma to paste II may be performed at two alternative sites: - Sanquin Plasma Products B.V, Plesmanlaan 125, 1066 CX Amsterdam, The Netherlands - C.A.F.-D.C.F. cvba-scrl, 107 de Tyras avenue, B-1120 Brussels, Belgium Subsequent processing of paste II to Drug Substance (including in-process, Drug Substance and stability testing) is performed at Sanquin.

Viral safety of Nanogam is based on the combined effects of selection donors, testing of plasma units and plasma pools for sensitive infection markers, and elimination of possible blood-borne viruses by effective virus inactivation by solvent-detergent treatment and removal of viruses by filtration steps in the manufacturing process.

II.3 Medicinal Product

Nanogam solution for infusion is a clear or slightly opalescent, colourless or slightly yellowish solution. The manufacturing process from Drug Substance to Drug Product is performed at Sanquin: Sanquin Plasma Products B.V., Plesmanlaan 125, 1066 CX Amsterdam, The Netherlands.

The development of the product has been described, the choice of excipients is justified and their functions explained. Different compositions were evaluated for the best choice of excipients in order to achieve a stable formula. The excipients glucose monohydrate and water for injections are according to Ph. Eur. quality. The formulated bulk product is sterile filtered and filled aseptically into dry het sterilised vials. The bioburden before sterile filtration is controlled with the limit of 10 cfu/100ml. Filling volumes are 10 ml, 25 ml, 50 ml, 100 ml, 200 ml and 300 ml. One pack size or a combination of different pack sizes may be dispensed from one bulk solution batch. The vials are stoppered and sealed immediately after the filling. The sterile filter is tested for integrity prior to and after the use. The vials are inspected visually, labelled and packed in the final sales packaging.

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The product specifications cover appropriate parameters for this dosage form. Validations of the analytical methods have been presented if the method is not compendial method. Batch analysis has been performed on 10 batches. The batch analysis results show that the finished products meet the specifications as proposed.

The conditions used in the stability studies are according to the ICH stability guideline. The stability is presented at 2-8 °C and for 6 months at 23- 27 °C. The stability of the finished product is stable and hence the proposed shelf life is 3 years when stored at 2-8 ºC (in a refrigerator) including storage for 6 months at ≤ 25 ºC is considered acceptable.

III. NON-CLINICAL ASPECTS

The nonclinical data in this line extension application for the product Nanogam 100 mg/mL is based onNanogam 50 mg/ml. For the completeness of the dossier and to support this line- extension (100 mg/mL), the applicant has provided a safety pharmacology study in rats with Nanogam (50 mg/ml). No vasoactive side effects were observed at dose of 250 mg/kg Nanogam. No additional studies are considered required. It is generally acknowledged that testing of human immunoglobulin preparations in animal models is of limited value.

Overview focusing on the nonclinical safety studies carried out with Nanogam (and other human Ig products) is considered adequate. These reveal that Nanogam and other comparable IVIg products have favourable safety profile.

Pharmacology To support the safety of Nanogam the Applicant included in the dossier a GLP- complaint safety pharmacology study in rats, which evaluated the vasoactive reactions with the treatment of Nanogam (50 mg/ml) (Study Report 041-041). Nanogam used in the study was taken from 10 production batches stored at 0, 6 and 12 months at 37°C, at 0, 12 and 24 months at 25°C and at 0,12, 24 and 36 months at 2-8°C. No substance –related significant adverse findings (hypertension or other vasoactive adverse responses) were noted after i.v. bolus of 250 mg/kg (5 ml/kg) Nanogam (50 mg/ml) and at an infusion rate of 6 ml/min in rats. As no significant vasoactive adverse effects were seen in this study, the study can be considered as a supportive for the safety of 100 mg/ml strength of Nanogam. No additional studies are considered required. It is generally acknowledged that testing of human immunoglobulin preparations in animal models is of limited value.

Pharmacokinetics N/A

Toxicology Nanogam is a IVIg product. No substance –related significant adverse findings were noted in a safety pharmacology study in rats with Nanogam (50 mg/ml) (Study Report 041-041). No toxicology studies were conducted and are considered not required. Adequate nonclinical safety data is provided.

Environmental Risk Assessment (ERA) The active substance is a natural substance (constituent from normal human blood, of naturally occurring immunoglobulins), the use of which will not alter the concentration or distribution of the substance in the environment. Therefore, Nanogam (100 mg/ml) is not expected to pose a risk to the environment.

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III.1 Discussion on the non-clinical aspects

In conclusion, from the nonclinical point of view, there are no major objections identified or concerns raised that require further clarification.

IV. CLINICAL ASPECTS

IV.1 Introduction

Primary immunodeficiency syndromes disorders (PID) result in increased susceptibility to recurrent infections, secondary to the underlying defects in humoral and/or cell-mediated immunity. To date, more than 100 different PID syndromes have been reported in the literature. The best described of these include X-linked agammaglobulinemia, common variable immune deficiency disease, selective IgA deficiency, severe combined immune deficiency, chronic granulomatous disease, Wiskott Aldrich syndrome, X-linked hyper IgM syndrome, DiGeorge syndrome, IgG subclass deficiency, ataxia telangiectasia, leukocyte adhesion deficiency, and complement deficiencies.

Therapeutic options for the treatment of infections in PID include standard antibiotic treatment and intravenous administration of IgG.

IGIV also has been used in the treatment of secondary immunodeficiencies such as those occurring in patients with multiple myeloma and B-cell chronic lymphocytic leukemia, acquired immunodeficiency syndrome (AIDS) or in patients undergoing bone marrow transplantation.

IGIV also has been used in the treatment of ITP. In addition to its use in therapy for PID and ITP IGIV products are also effective in the management of immune mediated disorders such as Kawasaki syndrome, and Guillain Barré syndrome.

The main mechanism of action of immunoglobulin in the case of immunodeficiency is replacement of functionally deficient immunoglobulins. In the case of immune-mediated diseases like ITP, the mechanism of action is less well understood. Several mechanisms have been postulated, such as reticuloendothelial blockade, an increase in T suppressor cells or natural killer cells, and a decrease in antibody synthesis.

Since the early 1980s, highly purified preparations of IgG for intravenous administration (IVIG) were developed by a number of manufacturers whereas the first products consisted of so-called modified products (modification of the Fc-part of the IgG to allow intravenous administration). Today non- modified, so-called native IVIGs are the standard of care for the replacement therapy of patients with primary immunodeficiency and they are part of the therapy regimen of the other indications mentioned before.

The marketing authorization for Nanogam 50 mg/ml was originally granted on 22 March 2004 in Finland. Subsequently, Mutual Recognition Procedure (MRP) with Sweden, Norway, Denmark, the Netherlands, Belgium and France as CMSs was completed on 1 December

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2004. In addition, Iceland was added as CMS through a Repeat Use Procedure in October 2014.

This is a decentralized line extension application submitted by Sanquin for the product Nanogam 100mg/ml based on Nanogam 50 mg/ml. Finland is acting as RMS and concerned member states (CMS) are Belgium and the Netherlands.

IV.2 Pharmacokinetics

Pharmacokinetics of Nanogam 50 mg/ml has been covered in the licensing procedure of the product. Two clinical trials (KB97003 and KB98001) were performed to support the original marketing authorisation application (MAA) of Nanogam 50mg/ml. The first trial was performed to study the kinetics, efficacy and safety of Nanogam 50mg/ml in hypogammaglobulinemia patients. Since the results of this study have been evaluated earlier in detail, these results are not discussed in this assessment report.

To support this line extension application, the pharmacokinetics was studied in one trial (MD2012.02) in PID patients. The purpose of the Applicant was to show the bioequivalence between Nanogam 50 mg/ml and Nanogam 100 mg/ml.

PK Study MD2012.02 This was a prospective, open-label, non-controlled, multicentre trial performed in the Netherlands. Pharmacokinetics after the infusion with Nanogam 50 mg/ml and after the fourth infusion with Nanogam 100 mg/ml was studied. 23 patients with primary a- or hypogammaglobulinemia who were stabilised on treatment with Nanogam 50 mg/ml were recruited.

PK parameters The mean maximum IgG concentration (Cmax) after intravenous administration of Nanogam 50 mg/ml IVIG product (Visit 1) and Nanogam 100 mg/ml IVIG product (Visit 5) in this study was comparable (17.8 g/L and 17.6 g/L); respectively. These levels are also comparable to those seen in healthy individuals. The AUC was also comparable after administration of Nanogam 50 mg/ml 100 mg/ml IVIG products (5612± 1265 h*g/L and 5462 ± 1189 h*g/L).

The mean half-life of Nanogam 50 mg/ml IVIG product was app. 28 days and comparable to that of Nanogam 100 mg/ml IVIG product; 26 days. This is also in line with a documented fact that individual IgG metabolism and concentrations can vary greatly in immunodeficiency patients compared to in healthy subjects, who generally have shorter IgG half-lives (~15-20 days).

IgG trough levels The mean IgG trough levels were comparable; 8.9 g/L (Nanogam 50 mg/ml) and 8.7 g/L (Nanogam 100 mg/ml). From the result provided, it seems most of the subjects had trough levels above 5 in all time measured time points (visits).

The IgG trough levels obtained are in line with scientific recommendations (> 5-6 g/L).

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Conclusions on pharmacokinetics

Study MD2012.02, a non-controlled, multicentre trial performed in the Netherlands investigating PK and safety to show the bioequivalence between Nanogam 50 mg/ml and Nanogam 100 mg/ml products. 23 patients with primary a- or hypogammaglobulinemia who were stabilised on treatment with Nanogam 50 mg/ml were recruited. PK parameters encompassed Cmax (g/L), tmax (h), t1/2term (h), and AUC [h*g/L] for serum concentration of IgG and were measured after infusion of Nanogam 50 mg/ml (Visit 1) and after the fourth infusion Nanogam 100 mg/ml (Visit 5); total IgG, IgG subclasses and IgG trough levels were determined at the beginning of the study and then prior to each of the 4 following infusions.

The mean maximum IgG concentration (Cmax) after intravenous administration of Nanogam 50 mg/ml IVIG product (Visit 1) and Nanogam 100 mg/ml IVIG product (Visit 5) in this study was comparable (17.8 g/L and 17.6 g/L); respectively. This result is also comparable to levels seen in healthy individuals. The AUC was also comparable after administration of Nanogam 50 mg/ml 100 mg/ml IVIG products (5612± 1265 h*g/L and 5462 ± 1189 h*g/L). The mean half-life of Nanogam 50 mg/ml IVIG product was app. 28 days and comparable to that of Nanogam 100 mg/ml IVIG product; 26 days. The mean IgG trough levels were comparable; 8.9 g/L (Nanogam 50 mg/ml) and 8.7 g/L (Nanogam 100 mg/ml).

The choice of population and the pharmacokinetic evaluation is largely in keeping with the Guideline (EMA/CHMP/BPWP/94033/2007 rev. 2) which was valid at the time of the study. In this Guideline (paragraph 8.3) it is stated that “Plasma concentration-time curve, half-life, area under the curve, volume of distribution, Cmax, Tmax, and elimination rate constant(s) should be measured in 20 adult PID patients assessed by repeated blood sampling after approximately 5-6 administrations of the product until immediately before the next infusion. These PK parameters should be compared to data obtained with the predecessor product. Study MD2012.02 is slightly shorter (4 infusions for determining trough levels), however, beyond the evaluation of trough levels the company has also provided a comparison of AUC, half-life, Cmax and tmax, between the 100 mg/ml and 50 mg/ml products.

Thus, the provided data are considered adequate for a comparative bridging of the Nanogam 100 mg/ml and 50 mg/ml products and the bioequivalence is thus demonstrated adequately. The IgG trough levels obtained are in line with the scientific recommendations (> 5-6 g/L) and deemed to be sufficient to protect the majority of PID patients from serious bacterial infections.

IV.3 Pharmacodynamics

No PD study is required in the relevant NfG as the replacement of IgG in PID patients has been established since the early 1950s. Also subjects with secondary immunodeficiencies, as classified in the current SPC, require replacement therapy with IgG since they present with similar symptoms to those found in PID patients.

IV.4 Clinical aspects

Two clinical trials (KB97003 and KB98001) were performed to support the original marketing authorisation application (MAA) of Nanogam 50mg/ml by the Finnish Red Cross Blood Transfusion Service, Helsinki, Finland (FRC). FRC manufactured the product used in

PAR Scientific discussion 7/11 the clinical trials. The trials were sponsored by Sanquin Plasma Products (formerly Sanquin, CLB), Amsterdam, the Netherlands. The first trial was performed to study the kinetics, efficacy and safety of Nanogam 50mg/ml in hypogammaglobulinemia patients. The second trial was performed in adult patients with chronic idiopathic thrombocytopenic purpura (ITP) to investigate the safety and efficacy of IVIG-L (Nanogam) in ITP. The results of these studies were compared with results obtained from literature. Since the results of these studies have been evaluated earlier in detail, these results are not discussed in this assessment report.

PK Study MD2012.02

This was a prospective, open-label, non-controlled, multicentre trial performed in the Netherlands. Pharmacokinetics after the infusion with Nanogam 50 mg/ml and after the fourth infusion with Nanogam 100 mg/ml was studied. 23 patients with primary a- or hypogammaglobulinemia who were stabilised on treatment with Nanogam 50 mg/ml were recruited. This study was not designed to obtain efficacy results and only safety results are presented here.

IV.5 Clinical safety

In total of 23 subjects received IVIG infusions on all planned visits, and were included in the safety population. In total, 92 infusions of Nanogam 100 mg/ml were administered to 23 subjects during 4 dosing intervals with an average of approximately 3 weeks per dosing interval.

Dosing interval ranged between 13 and 43 days during the study. Fifteen (15) subjects were infused with Nanogam IVIG product once in approximately every 3 weeks, and 4 subjects once in approximately every 2 weeks. Four (4) subjects had dosing intervals of approximately 4 weeks. Dosing intervals during the study were comparable to those before start of the study for the individual subjects.

The cumulative dose of 100 mg/ml IVIG Nanogam product was 2390 g in a total of 23 subjects during 4 dosing intervals with an average of approximately 3 weeks per dosing interval.

The treatment with Nanogam 100mg/ml with comparable IVIG dose and infusion rate than before with Nanogam 50mg/ml seem to be feasible. The fact that that average infusion duration with Nanogam 100mg/ml was shorter that Nanogam 50mg/ml is acknowledged.

Adverse events

Seventeen (17) out of 23 patients (73.9%) experienced at least one AE during the whole trial. Of thirty- five AEs, thirty-three (33) treatment emergent AEs were reported during the study. Of these treatment emergent AES, 7 emerged during the treatment period with 50 mg/mL Nanogam IVIG product (period 1), and 26 emerged during the treatment period with 100 mg/mL Nanogam IVIG product.

In total sixteen (16) out of 23 patients experienced at least one treatment emergent AE. Three AEs were considered possibly related to IVIG treatment (3/33). This concern three of the four incidences of leukopenia, which occurred in one subject each, in treatment periods with 100 mg/mL Nanogam IVIG product (period 3, 4 and 5). For these subjects, total IgG

PAR Scientific discussion 8/11 exposure (Cmin, Cmax, AUC) was in range with IgG exposure of the other subjects. Leukopenia occurred directly after infusion. The Applicant states that the incidences of leukopenia had no clinical consequences and symptoms.

Most pf the AEs found in this study are in line with the previous experience with IVIGs use. However, four incidences of leukopenia were found. The Applicant states that these three out of four of this AE were considered possibly related to IVIG treatment. It would ideal to know leukocyte differential count for each of these three cases since neutropenia has been found after high-dose intravenous immunoglobulin therapy. In subjects with impaired immunity neutropenia could be potentially of concern.

In addition, this AE has been mentioned in related to other IVIG treatments (i.e. with Kiovig under SOC Investigations, Frequency Uncommon). Thus the Applicant is asked to include this new AE to the SPC section 4.8 and provide an adequate calculation of the frequency of this AE.

Serious adverse events and deaths

One subject died following cardiac arrest 8 days after the last study related visit and 29 days after the last IVIG infusion in this study. This subject had a known insufficiency of coronary/cerebral circulation, which was considered a major protocol deviation. The investigator considered the event as not related to the study medication. Four (4) other SAEs were reported, all for the subject who died.

The narratives for the SAEs were provided and the evaluation of the applicant can be endorsed. It seems that the subject who died had several co-morbidities. Since all SAEs were found in this same subject and all four of them were infections it seems reasonable that this subject received IVIGs to prevent / “treat” these serious conditions. The Applicant`s view that this event was not related to the study medication is acceptable.

Laboratory findings

There were no relevant new clinical safety signs emerging from the laboratory data in addition to leukopenia discussed earlier.

Conclusions on safety

The safety data from for the Nanogam 100mg/ml product encompassed 23 PID patients. In total 92 infusions of Nanogam 100 mg/ml were administered to 23 subjects during 4 dosing intervals with an average of approximately 3 weeks per dosing interval. The average dose per administration was 26 g per subject, 0.4 g per kg body weight.

The safety profile was similar with previous experience of Nanogam 50mg/ml. The main AEs were related to the underlying disorder as reflected in the various types of infections. In total 35 AEs occurred in 17 patients (73.9%), of which 33 AEs in 16 subjects (69.6%) were treatment emergent AEs.

Three (3) out of 4 accounts of leukopenia were judged by the investigator to be at least possibly related to trial medication intake. This AE has been mentioned in related to other IVIG treatments (i.e. with Kiovig under SOC Investigations, Frequency Uncommon). Thus the Applicant was asked to include this new AE to the SPC section 4.8 and provide an adequate calculation of the frequency of this AE.

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The Applicant has updated the SPC section 4.8 accordingly and this AE has been now added to as: SOC Investigations, PT white blood cell counts decreased. The frequency is “common” (≥1/100 to <1/10): 3 cases in 92 infusions (1/31).

There were no notable differences in the frequency and incidence per SOC of the AEs between the Nanogam 50 mg/mL (period 1) and the Nanogam 100 mg/ml treatment (periods 2 to 5).

Seen in conjunction with the previous data from the Nanogam 50 mg/ml studies, the data is considered to be sufficient for the bridging concept between the 2 products.

IV.6 Risk Management Plan

The MAH has submitted a risk management plan, in accordance with the requirements of Directive 2001/83/EC as amended, describing the pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to Nanogam 100 mg/ml.

The RMP v.2 of Nanogam (Human normal immunoglobulin product for intravenous administration) was initially endorsed by the RMS. Comments were received from a CMS which suggested that proposed potential risk ‘medication errors due to wrong dose’ is merged with the proposed identified risk ‘medication errors due to wrong route of administration’ as the identified risk ‘medication errors (among others wrong route of administration, wrong dose)’. The MAH has responded that both safety concerns on medication errors were removed from the Nanogam RMP during a previous variation procedure and they reappeared by mistake. Thus, the MAH suggested to remove the safety concerns on medication errors from the RMP, rather than merging them into one safety concern.The MAH’s responses are endorsed by the RMS and an updated RMP should be submitted for approval during this procedure. With regard to the proposed SPC update in section 4.8 with white blood cell counts decreased, the MAH has also proposed to amend the RMP. Not all the events in section 4.8 are to be included as safety concerns in the RMP. The MAH is asked to clarify this, i.e, is this a new important risk?

In its response, the MAH has submitted an updated RMP v 2.1. As proposed the MAH has removed the important identified risk of medication error due to wrong route of administration and the important potential risk of medication error due to wrong dose. In addition ‘white blood cell count decreased’ was removed from the Summary of safety concern. The RMP v 2.1 is approvable.

IV.7 Discussion on the clinical aspects

The provided data are considered adequate for a comparative bridging of the Nanogam 100 mg/ml and 50 mg/ml products and the bioequivalence is thus demonstrated adequately. The choice of population and the pharmacokinetic evaluation is largely in keeping with the Guideline (EMA/CHMP/BPWP/94033/2007 rev. 2) which was valid at the time of the study. It is also in line with the scientific advice given by the Finnish Medicines Agency (FIMEA).

PAR Scientific discussion 10/11 Regarding the safety, there were no notable differences in the frequency and incidence per SOC of the AEs between the Nanogam 50 mg/mL (period 1) and the Nanogam 100 mg/ml treatment (periods 2 to 5).

No new SAE´s or severe safety concerns were identified. The adverse reactions to IVIGs are well known and have been described in the SPC. However, one new AE (leucopenia), which has been mentioned in related to other IVIG treatments was identified. The applicant has now included this AE to the SPC section 4.8 (Investigations, PT white blood cell counts decreased) with frequency “common”.

V. USER CONSULTATION

The Applicant refers to readability test is performed and finished in May 2008 (Nanogam 50mg/ml). Since the text is identical compared to Nanogam 100mg/ml this is considered acceptable.

VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION

In conclusion, the benefit risk profile is positive.

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