Privigen - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Privigen 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 25 ml solution contains: 2.5 g human normal immunoglobulin

Each vial of 50 ml solution contains: 5 g human normal immunoglobulin

Each vial of 100 ml solution contains: 10 g human normal immunoglobulin

Each vial of 200 ml solution contains: 20 g human normal immunoglobulin

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

Distribution of the IgG subclasses (approx. values):

IgG1.........­.............­.69 %

IgG2.........­.............­.26 %

IgG3.........­.............­.. 3 %

IgG4.........­.............­.. 2 %

The maximum IgA content is 25 micrograms/ml.

• *Produced from the plasma of human donors.

Excipients with known effects:

Privigen contains approximately 250 mmol/L (range: 210 to 290) of L-proline.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Solution for infusion.

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

Privigen is isotonic, with an approximate osmolality of 320 mOsmol/kg.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

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

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

• – 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-Barre syndrome.

• – Kawasaki disease (in conjunction with acetylsalicylic acid; see section 4.2.).

• – Chronic inflammatory demyelinating polyneuropathy (CIDP). Only limited experience is available of use of intravenous immunoglobulins in children with CIDP.

• – Multifocal motor neuropathy (MMN)

4.2 Posology and method of administration

Replacement therapy should be commenced 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.

In replacement therapy the dose may need to be individualised for each patient depending 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 (PID) syndromes

The dose regimen should achieve a trough IgG level (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 to occur. The recommended starting dose is 0.4 to 0.8 g/kg body weight (bw) given once, followed by at least 0.2 g/kg bw every 3 to 4 weeks.

The dose required to achieve a trough level of IgG of6 g/l is of the order of 0.2 to 0.8 g/kg bw/month.

The dosage interval when steady state has been reached varies from 3 to 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 dose regimen should achieve a trough IgG level (measured before the next infusion) of at least 6 g/l or within the normal reference range for the population age. The recommended dose is 0.2 – 0.4 g/kg bw 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 (ITP)

There are two alternative treatment schedules:

• • 0.8 to 1g/kg bw given on day 1; this dose may be repeated once within 3 days
• • 0.4 g/kg bw given daily for 2 to 5 days.

The treatment can be repeated if relapse occurs.

Guillain-Barre syndrome

0.4 g/kg bw/day over 5 days (possible repeat of dosing in case of relapse).

Kawasaki disease

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

Chronic inflammatory demyelinating polyneuropathy (CIDP)

The recommended starting dose is 2 g/kg bw divided over 2 to 5 consecutive days followed by maintenance doses of 1 g/kg bw over 1 to 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 given 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 insufficient 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. 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:

Indication	Dose	Frequency of injections
Replacement therapy
Primary immunodeficiency syndromes (PID)	starting dose: 0.4 – 0.8 g/kg bw maintenance dose: 0.2 – 0.8 g/kg bw	every 3 to 4 weeks to obtain IgG trough levels of at least 6 g/l
Secondary immunodeficiencies (as defined in 4.1)	0.2 – 0.4 g/kg bw	every 3 to 4 weeks to obtain IgG trough levels of at least 6 g/l
Immunomodulation
Primary immune thrombocytopenia (ITP)	0.8 – 1 g/kg bw or 0.4 g/kg bw/d	on day 1, possibly repeated once within 3 days for 2 to 5 days
Guillain-Barre syndrome	0.4 g/kg bw/d	for 5 days
Kawasaki disease	2 g/kg bw	in one dose in association with acetylsalicylic acid
Chronic inflammatory demyelinating polyneuropathy (CIDP)	starting dose: 2 g/kg bw maintenance dose: 1 g/kg bw	in divided doses over 2 to 5 days every 3 weeks over 1 to 2 days
Multifocal Motor Neuropathy (MMN)	starting dose : 2 g/kg bw maintenance dose: 1 g/kg bw or 2 g/kg bw	over 2 to 5 consecutive days every 2 to 4 weeks or every 4 to 8 weeks over 2 to 5 days

• *The dose is based on the dose used in the clinical studies conducted with Privigen. The duration of treatment beyond 25 weeks should be subject to the physician’s dis­cretion based upon the patient response and maintenance response in the long-term. The dosing and intervals may have to be adapted according to the individual course of the disease.

Paediatric population

The posology in children and adolescents (0–18 years) is not different from 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.

Privigen should be infused intravenously at an initial infusion rate of 0.3 ml/kg bw/hr for approximately 30 min. If well tolerated (see section 4.4), the rate of administration may gradually be increased to 4.8 ml/kg bw/hr.

In PID patients who have tolerated the infusion rate of 4.8 ml/kg bw/hr well, the rate may be further gradually increased to a maximum of 7.2 ml/kg bw/hr.

If dilution prior to infusion is desired, Privigen may be diluted with 5% glucose solution to a final concentration of 50 mg/ml (5%). For instruction, see section 6.6.

4.3 Contraindications

Hypersensitivity to the active substance (human immunoglobulins) or to any of the excipients listed in section 6.1 (see also section 4.4).

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

Patients with hyperprolinaemia type I or II.

4.4 Special warnings and precautions for use

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.

Certain severe adverse reactions may be related to the rate of infusion. The recommended infusion rate given under section 4.2 must be closely followed. Patients must be closely monitored and carefully observed for any symptoms throughout the infusion period.

Certain adverse reactions may occur more frequently:

• – in case of high rate of infusion,

• – in patients with hypogammaglobu­linaemia or agammaglobuli­naemia, with or without IgA deficiency,

• – in patients who receive human normal immunoglobulin for the first time or, in rare cases, when the human normal immunoglobulin product is switched or when there has been a long interval since the previous infusion.

Potential complications can often be avoided by ensuring that patients:

• – are not sensitive to human normal immunoglobulin by initially infusing the product slowly (0.3 ml/kg bw/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 order to detect potential adverse signs. All other patients should be observed for at least 20 minutes after administration.

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

In 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 section 4.5.).

4.5 Interaction with other medicinal products and other forms of interaction

Live attenuated virus vaccines

Immunoglobulin administration may impair for a period of at least 6 weeks and up to 3 months the efficacy of live attenuated virus vaccines such as measles, rubella, mumps, and varicella. After administration of this medicinal product, an interval of 3 months should elapse before vaccination with live attenuated virus vaccines. In the case of measles, this impairment may persist for up to 1 year. Therefore, patients receiving measles vaccine should have their antibody status checked.

Loop diuretics

Avoidance of concomitant use of loop diuretics.

Paediatric population

Although limited data is available, it is expected that the same interactions may occur in the paediatric population.

4.6 Fertility, pregnancy and lactation

Pregnancy

The safety of this medicinal product for use in human pregnancy has not been established in controlled clinical trials and therefore should only be given with caution to pregnant women and breast-feeding mothers. IVIg products have been shown to cross the placenta, increasingly during the third trimester. Clinical experience with immunoglobulins suggests that no harmful effects on the course of pregnancy, or on the foetus and the neonate are to be expected.

Experimental studies of the excipient L-proline carried out in animals found no direct or indirect toxicity affecting pregnancy, embryonal or foetal development.

Breast-feeding

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

Fertility

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

4.7 Effects on ability to drive and use machines

Privigen has minor influence on the ability to drive and use machines, e.g. dizziness (see section 4.8). Patients who experience adverse reactions during treatment should wait for these to resolve before driving or operating machines.

4.8 Undesirable effects

Summary of the safety profile

Adverse reactions such as chills, headache, dizziness, fever, vomiting, allergic reactions, nausea, arthralgia, low blood pressure and moderate low back pain may occur occasionally in connection with intravenous administration of human immunoglobulin.

Rarely human normal immunoglobulins may cause a sudden fall in blood pressure and, in isolated cases, anaphylactic shock, even when the patient has shown no hypersensitivity to previous administration.

Cases of reversible aseptic meningitis and rare cases of transient cutaneous reactions (including cutaneous lupus erythematosus – frequency unknown) have been observed with human normal immunoglobulin.

Reversible haemolytic reactions have been observed in patients, especially those with blood groups A, B, and AB in immunomodulatory treatment. Rarely, haemolytic anaemia requiring transfusion may develop after high dose IVIg treatment (see section 4.4).

Increase in serum creatinine level and/or acute renal failure have been observed.

Very rarely: Transfusion related acute lung injury (TRALI) and thromboembolic reactions such as myocardial infarction, stroke, pulmonary embolism and deep vein thromboses.

Tabulated list of adverse reactions

Seven clinical studies were performed with Privigen, which included patients with PID, ITP and CIDP. In the pivotal PID study, 80 patients were enrolled and treated with Privigen. Of these, 72 completed the 12 months of treatment. In the PID extension study, 55 patients were enrolled and treated with Privigen. Another clinical study included 11 PID patients in Japan. Two ITP studies were performed with 57 patients each. Two CIDP studies were performed with 28 and 207 patients, respectively.

Most adverse drug reactions (ADRs) observed in the seven clinical studies were mild to moderate in nature.

The following table shows an overview of the ADRs observed in the seven clinical studies categorized according the MedDRA System Organ Class (SOC), Preferred Term Level (PT) and frequency.

Frequencies were evaluated according to the following conventions: 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). For spontaneous post-marketing ADRs, the reporting frequency is categorized as unknown.

Within each frequency grouping, undesirable effects are presented in order of decreasing frequency.

MedDRA System Organ Class (SOC)	Adverse Reaction	Frequency per patient	Frequency per infusion
Infections and infestations	Aseptic meningitis	Uncommon	Rare

MedDRA System Organ Class (SOC)	Adverse Reaction	Frequency per patient	Frequency per infusion
Blood and lymphatic system disorders	Anaemia, haemolysis (including haemolytic anaemia)ß, leukopenia	Common	Uncommon
	Anisocytosis (including microcytosis)	Uncommon	Uncommon
	Thrombocytosis		Rare
	Decreased neutrophil count	Unknown	Unknown
Immune system disorders	Hypersensitivity	Common	Uncommon
	Anaphylactic shock	Unknown	Unknown
Nervous system disorders	Headache (including sinus headache, migraine, head discomfort, tension headache)	Very common	Very common
	Dizziness (including vertigo)	Common	Uncommon
	Somnolence	Uncommon	Uncommon
	Tremor		Rare
Cardiac disorders	Palpitations, tachycardia	Uncommon	Rare
Vascular disorders	Hypertension, flushing (including hot flush, hyperaemia)	Common	Uncommon
	Hypotension		Rare
	Thromboembolic events, vasculitis (including peripheral vascular disorder)	Uncommon	Rare
	Transfusion related acute lung injury	Unknown	Unknown
Respiratory, thoracic and mediastinal disorders	Dyspnoea (including chest pain, chest discomfort, painful respiration)	Common	Uncommon
Gastrointestinal disorders	Nausea, vomiting, diarrhoea	Common	Common
	Abdominal pain		Uncommon
Hepatobiliary disorders	Hyperbilirubinaemia	Common	Rare
Skin and subcutaneous tissue disorders	Skin disorder (including rash, pruritus, urticaria, maculo-papular rash, erythema, skin exfoliation)	Common	Common
Musculoskeletal and connective tissue disorders	Myalgia (including muscle spasms, musculoskeletal stiffness, musculoskeletal pa­in)	Common	Uncommon
Renal and urinary disorders	Proteinuria, increased blood creatinine	Uncommon	Rare
	Acute renal failure	Unknown	Unknown
General disorders and administration site conditions	Pain (including back pain, pain in extremity, arthralgia, neck pain, facial pain) pyrexia (including chills), influenza like illness (including nasopharyngitis, pharyngolaryngeal pain, oropharyngeal blistering, throat tightness)	Very common	Common
	Fatigue	Common	Common
	Asthenia (including muscular weakness)		Uncommon
	Injection site pain (including infusion site discomfort)	Uncommon	Rare
Investigations	Decreased haemoglobin (including decreased red blood cell count, decreased haematocrit), Coombs'	Common	Uncommon

MedDRA System Organ Class (SOC)	Adverse Reaction	Frequency per patient	Frequency per infusion
	(direct) test positive, increased alanine aminotransferase, increased aspartate aminotransferase, increased blood lactate dehydrogenase

p The frequency is calculated based on studies completed prior to implementation of the Immunoaffinity Chromatography isoagglutinin reduction step (IAC) into Privigen production. In a Post-Authorization Safety Study (PASS): “Privigen Use and Haemolytic Anaemia in Adults and Children and the Privigen Safety Profile in Children with CIDP – An Observational Hospital-Based Cohort Study in the US”, assessing data of 7,759 patients who received Privigen identifying 4 haemolytic anaemia cases after IAC versus 9,439 patients who received Privigen identifying 47 haemolytic anaemia cases prior to IAC (baseline), an 89% statistically significant reduction in the overall rate of probable haemolytic anaemia was demonstrated based on an incidence rate ratio of 0.11 adjusted for in-/outpatient setting, age, sex, Privigen dose and indication for Privigen use (one-sided p-value <0.01). Probable cases of haemolytic anaemia were defined by an International Classification of Disease (ICD)-9 or ICD-10 hospital discharge code specific for haemolytic anaemia. Possible cases of haemolytic anaemia consisted of an unspecified transfusion reaction identified via ICD-9 or ICD-10 discharge codes or via review of hospital charge descriptions in temporal association with a haptoglobin, a direct antiglobulin test or indirect antiglobulin performed in the workup of haemolytic anaemia.

For safety with respect to transmissible agents and additional details on risk factors, see section 4.4.

Paediatric Population

In Privigen clinical studies with paediatric patients, the frequency, nature and severity of adverse reactions did not differ between children and adults. In post marketing reports it is observed that the proportion of haemolysis cases to all case reports occurring in children is slightly higher than in adults. Please refer to section 4.4 for details on risk factors and monitoring recommendations.

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 listed in

4.9 Overdose

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

5. PHARMACOLOGICAL PROPERTIES5.1 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 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 and thus help against infections.

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

The safety and efficacy of Privigen was evaluated in 7 prospective, open-label, single-arm, multicenter studies performed in Europe (ITP, PID and CIDP studies), Japan (PID and CIDP studies), and the US (PID and CIDP studies).

Additional safety data were collected in a Post-Authorization Safety Study (PASS), an observational multicentre trial in patients with various immunological conditions performed in the US.

PID

The PID pivotal study included a total of 80 patients aged between 3 and 69 years old. 19 children (3 to 11 years), 12 adolescents (12 to 16 years) and 49 adults were treated with Privigen over 12 months. 1038 infusions were administered, 272 (in 16 patients) in the 3-week schedule and 766 (in 64 patients) in the 4-week schedule. The median doses administered for the 3-week and 4-week treatment schedules were almost identical to each other (428.3 vs. 440.6 mg IgG/ kg bw).The PID extension study included a total of 55 patients aged between 4 and 81 years old. 13 children (3 to 11 years), 8 adolescents (12 to 15 years) and 34 adults were treated with Privigen over 29 months. 771 infusions were administered and the median dose administered was 492.3 mg IgG/kg bw.

ITP

In the ITP pivotal study, in total 57 patients aged between 15 and 69 years old were treated with 2 infusions of Privigen for a total of 114 infusions. The scheduled dose of 1 g/kg bw per infusion was closely adhered to in all patients (median 2 g IgG/kg bw).

In the second ITP study, 57 patients with ITP (baseline platelet counts <30×109/ l) aged between 18 and 65 years were treated with Privigen at 1 g/kg bw. On day 3 patients could receive a second dose of 1 g/ kg bw, for patients with a platelet count of < 50×109 / l on day 3 this second dose was mandatory. Overall, in 42 subjects (74 %) the platelet count increased at least once to > 50×109 / l within 6 days after the first infusion, which was well within the expected range. A second dose in subjects with platelet counts > 50×109 /l after the first dose provided a relevant additional benefit in terms of higher and longer-lasting increases in platelet counts compared to a single dose. In subjects with platelet counts < 50×109 / l after the first dose, 30% showed a platelet response of > 50×109 / l after the mandatory second dose.

CIDP

In the first CIDP study, a prospective multicenter open label trial (Privigen impact on mobility and autonomy PRIMA study), 28 patients (13 subjects who have previously received IVIG and 15 subjects not) were treated with a Privigen loading dose of 2g/kg bw given over 2–5 days followed by 6 maintenance doses of 1g/kg bw over 1–2 days every three weeks. Previously treated patients were withdrawn from IVIG until confirmed deterioration before start of Privigen. On the adjusted 10 point INCAT (Inflammatory Neuropathy Cause and Treatment) scale a clinically meaningful improvement of at least 1-point from baseline to treatment week 25 was observed in 17 out of 28 patients. The INCAT responder rate was 60.7% (95% confidence interval [42.41, 76.4]). 9 patients responded after receiving the initial induction dose by week 4, 16 patients responded by week 10.

Muscle strength as measured by the MRC (Medical Research Council) Score improved in all patients by 6.9 points (95% confidence interval [4.11, 9.75], in previously treated patients by 6.1 points (95% confidence interval [2.72, 9.44]) and in untreated patients by 7.7 points (95% confidence interval [2.89, 12.44]). The MRC responder rate, an increase of at least 3 points, was 84.8% which was similar in previously treated (81.5% [58.95, 100.00]) and untreated (86.7% [69.46, 100.00]) patients.

In patients defined as INCAT non-responders, muscle strength improved by 5.5 points (95% confidence interval [0.6, 10.2]) as compared to INCAT responders (7.4 points (95% confidence interval [4.0, 11.7])

In a second prospective, multicenter randomized, placebo-controlled clinical study (Polyneuropathy and Treatment with Hizentra, PATH trial), 207 subjects with CIDP were treated with Privigen in the prerandomization phase of the study. Subjects all with IVIg pretreatment of at least 8 weeks and with an IVIg-dependence confirmed by clinically evident deterioration during an IVIg withdrawal phase of up to 12 weeks, received a Privigen loading dose of 2 g/kg bw followed by up to 4 Privigen maintenance doses of 1 g/kg bw every 3 weeks for up to 13 weeks.

Following clinical deterioration during IVIg withdrawal, clinical improvement of CIDP was primarily defined by a decrease of > 1 point at the adjusted INCAT score. Additional measures of CIDP improvement were an increase in R-ODS (Rasch-built Overall Disability Scale) score of >4 points, a mean grip strength increase of > 8 kPa, or an MRC sum score increase of > 3 points. Overall, 91 % of subjects (188 patients) showed improvement in at least one of the criteria above by week 13.

By adjusted INCAT score, the responder rate by week 13 was 72.9 % (151 / 207 patients), with 149 patients responding already by week 10. A total of 43 of the 207 patients achieved a better CIDP status as assessed by the adjusted INCAT score compared to their CIDP status at study entry.

The mean improvement at the end of the treatment period compared to reference visit was 1.4 points in the PRIMA (1.8 points in IVIg pretreated subjects) and 1.2 points in PATH study.

In PRIMA, the percentage of responders in the overall Medical Research Council (MRC) score (defined as an increase by > 3 points) was 85 % (87 % in the IVIg-untreated and 82 % in IVIg-pretreated) and 57 % in PATH. The overall median time to first MRC sum score response in PRIMA was 6 weeks (6 weeks in the IVIg-untreated and 3 weeks in the IVIg-pretreated) and 9.3 weeks in PATH. MRC sum score in PRIMA improved by 6.9 points (7.7 points for IVIg-untreated and 6.1 points for IVIg-pretreated) and by 3.6 points in PATH.

The grip strength of the dominant hand improved by 14.1 kPa (17.0 kPa in IVIg-untreated and 10.8 kPa in IVIg pretreated subjects) in the PRIMA study, while in PATH the grip strength of the dominant hand improved by 12.2 kPa. For the non dominant hand similar results were observed in both PRIMA and PATH trials.

The efficacy and safety profile in the PRIMA and the PATH study in CIDP patients were overall comparable.

Post-Authorisation Safety Study (PASS)

In an observational hospital-based cohort Post-Authorisation Safety Study (PASS), the risk of haemolytic anaemia following Privigen therapy was evaluated in patients with various immunological conditions from 1 January 2008 to 30 April 2019. The risk of haemolytic anaemia was assessed prior (baseline) and after the implementation of a risk minimisation measure, the introduction of the Immunoaffinity Chromatography (IAC) step in the Privigen manufacturing process. Probable cases of haemolytic anaemia were defined by an ICD-9 or ICD-10 hospital discharge code specific for haemolytic anaemia. (Possible cases of haemolytic anaemia consisted of an unspecified transfusion reaction identified via ICD-9 or ICD-10 discharge codes or via review of hospital charge descriptions in temporal association with a haptoglobin, a direct antiglobulin test or indirect antiglobulin performed in the workup of haemolytic anaemia).

A statistically significant rate reduction of 89% of haemolytic anaemia (based on an incidence rate ratio of 0.11; adjusted for in-/outpatient setting, age, sex, Privigen dose and indication for Privigen use; one-sided p-value <0.01) was observed after implementation of the IAC step compared to baseline:

	Baseline	IAC
Period*	1. January 2008 31. December 2012	1. October 2016 30. April 2019
Median anti-A titers£	1:32	1:8
Median anti-B titers£	1:16	1:4
Probable haemolytic anaemia“ cases	47	4
Patient number (n)	n=9439	n=7759
Crude incidence rate of probable haemolytic anaemia“ per 10.000 patient-days at risk	0.74 95% CI&: 0.54–0.98	0.08 95% CI: 0.02–0.20
Incidence rate reduction of probable haemolytic anaemia “ versus baseline	–	89%
Adjusted0 incidence rate ratio for haemolytic anaemia versus baseline	–	0.11 95% CI: 0.04–0.31, one-sided p-value: <0.01

* The exclusion of human blood plasma donors with high anti-A titres performed between 1. October 2013 and 31. December 2015 as the initial risk minimisation measure for haemolytic anaemia indicated a 38% reduction in probable haemolytic anaemia incidence versus baseline and was subsequently replaced by the IAC step in the Privigen manufacturing process, as provided above.

£ Median isoagglutinin titers measured by direct testing method according to Ph.Eur

aProbable haemolytic anaemia case: defined by an ICD-9 or ICD-10 hospital discharge code specific for haemolytic anaemia and the occurrence during the time interval from the first infusion up to 30 days after the last infusion, if >1 Privigen infusions were administered

& Confidence interval

' Adjusted for: in-/outpatient setting, age, sex, Privigen dose and indication for Privigen use

The reduction in probable haemolytic anaemia incidence rate after IAC implementation versus baseline was especially pronounced in patients treated with Privigen doses >0.75 g/kg bw.

Additionally, 28 paediatric patients with CIDP <18 years of age were identified throughout the entire study period from 1 January 2008 to 30 April 2019. No paediatric patients with CIDP given a total of 486 Privigen administrations experienced haemolytic anaemia, AMS, acute renal failure, severe anaphylactic reaction or a thromboembolic event. Two patients experienced a moderate anaphylactic reaction, equating to 0.4% of all Privigen administrations.

Paediatric population

No differences were observed in the pharmacodynamic properties and safety profile between adult and paediatric study patients.

5.2 Pharmacokinetic properties

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

IgG and IgG complexes are broken down in the cells of the reticuloendothelial system. The half-life may vary from patient to patient. The pharmacokinetic parameters for Privigen were determined in a clinical study in PID patients (see section 5.1). 25 patients (aged 13–69 years) participated in the pharmacokinetic (PK) assessment. In this study, the median half-life of Privigen in PID patients was 36.6 days. In an extension of this study, 13 PID patients (aged 3–65 years) participated in a PK substudy. The results of this study show the median half-life of Privigen to be 31.1 days (see table below).

Pharmacokinetic parameters of Privigen in PID patients

Parameter	Pivotal Study (N= 25) ZLB03_002CR Median (Range)	Extension Study (N=13) ZLB05_006CR Median (Range)
Cmax (peak, g/l)	23.4 (10.4–34.6)	26.3 (20.9–32.9)
Cmm (trough, g/l)	10.2 (5.8–14.7)	12.3 (10.4–18.8) (3-week schedule) 9.4 (7.3–13.2) (4-week schedule)
t>/2 (days)	36.6 (20.6–96.6)	31.1 (14.6–43.6)

Cmax, maximum serum concentration; Cmm, trough (minimum level) serum concentration; t>/2, elimination half-life

Paediatric population

No differences were seen in the pharmacokinetic parameters between adult and paediatric study patients with PID. There are no data on pharmacokinetic properties in paediatric patients with CIDP.

5.3 Preclinical safety data

Immunoglobulins are a normal constituent of the human body. L-proline is a physiological, nonessential amino acid.

The safety of Privigen has been assessed in several preclinical studies, with particular reference to the excipient L-proline. Some published studies pertaining to hyperprolinaemia have shown that longterm, high doses of L-proline have effects on brain development in very young rats. However, in studies where the dosing was designed to reflect the clinical indications for Privigen, no effects on brain development were observed. Non-clinical data reveal no special risk for humans based on safety pharmacology and toxicity studies.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

L-proline

Water for injections

Hydrochloric acid (for pH-adjustment)

Sodium hydroxide (for pH adjustment)

6.2 Incompatibilities

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

6.3 Shelf life

3 years

Stability after first opening:

Once the vial has been broached, its contents should be used promptly. Because the solution contains no preservative, Privigen should be infused immediately.

Stability after dilution:

If the product is diluted to lower concentrations (see section 6.6), immediate use after dilution is recommended. The in-use stability of Privigen after dilution with a 5% glucose solution to a final concentration of 50 mg/ml (5%) has been demonstrated for 10 days at 30°C; however, the microbial contamination aspect was not studied.

6.4 Special precautions for storage

Do not store above 25 °C.

Do not freeze.

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

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

6.5 Nature and contents of container

25 ml of solution in a single vial (type I glass), with a stopper (elastomeric), a cap (aluminium crimp), a flip off disc (plastic), label with integrated hanger.

50 or 100 ml of solution in a single vial (type I or II glass), with a stopper (elastomeric), a cap (aluminium crimp), a flip off disc (plastic), label with integrated hanger.

200 or 400 ml of solution in a single vial (type II glass), with a stopper (elastomeric), a cap (aluminium crimp), a flip off disc (plastic), label with integrated hanger.

Pack sizes

1 vial (2.5 g/25 ml, 5 g/50 ml, 10 g/100 ml, 20 g/200 ml or 40 g/400 ml), 3 vials (10 g/100 ml or 20 g/200 ml).

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Privigen comes as a ready-to-use solution in single-use vials. The product should be brought to room temperature (25°C) before use. A vented infusion line should be used for the administration of Privigen. Flushing of the infusion tubes with physiological saline or 5% glucose solution is permitted. Always pierce the stopper at its centre, within the marked area.

The solution should be clear or slightly opalescent and colourless or pale yellow. Solutions that are cloudy or have deposits should not be used.

If dilution is desired, 5% glucose solution should be used. For obtaining an immunoglobulin solution of 50 mg/ml (5%), Privigen 100 mg/ml (10%) should be diluted with an equal volume of the 5% glucose solution. Aseptic technique must be strictly observed during the dilution of Privigen.

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

7. MARKETING AUTHORISATION HOLDER

CSL Behring GmbH

Emil-von-Behring-Strasse 76

D-35041 Marburg

Germany

8. MARKETING AUTHORISATION NUMBERS

EU/1/08/446/001

EU/1/08/446/002

EU/1/08/446/003

EU/1/08/446/004

EU/1/08/446/005

EU/1/08/446/006

EU/1/08/446/007

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 25 April 2008

Date of latest renewal: 28 November 2017