PRIVIGEN 100mg / ml solution for infusion medication leaflet

Privigen 100 mg/ml solution for infusion

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.

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

For the full list of excipients, see section 6.1.

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.

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

- Primary immunodeficiency syndromes (PID) with impaired antibody production (seesection 4.4).

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

* PSAF = failure to mount at least a 2-fold rise in IgG antibody titre to pneumococcal polysaccharideand 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 surgeryto correct the platelet count.

- Guillain-Barré syndrome.- Kawasaki disease (in conjunction with acetylsalicylic acid; see section 4.2.).- Chronic inflammatory demyelinating polyneuropathy (CIDP). Only limited experience isavailable of use of intravenous immunoglobulins in children with CIDP.- Multifocal motor neuropathy (MMN)

Replacement therapy should be commenced and monitored under the supervision of a physicianexperienced in the treatment of immunodeficiency.

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 theclinical response. Dose based on bodyweight may require adjustment in underweight or overweightpatients.

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 least6 g/l or within the normal reference range for the population age. Three to six months are requiredafter the initiation of therapy for equilibration to occur. The recommended starting dose is 0.4 to0.8 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 of 6 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. Toreduce the rate of bacterial infections, it may be necessary to increase the dosage and aim for highertrough levels.

Secondary immunodeficiencies (as defined in 4.1)

The dose regimen should achieve a trough IgG level (measured before the next infusion) of at least6 g/l or within the normal reference range for the population age. The recommended dose is0.2 - 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 maybe necessary in patients with persisting infection; a dose decrease can be considered when the patientremains 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-Barré syndrome0.4 g/kg bw/day over 5 days (possible repeat of dosing in case of relapse).

Kawasaki disease2.0 g/kg bw should be administered as a single dose. Patients should receive concomitant treatmentwith acetylsalicylic acid.

Chronic inflammatory demyelinating polyneuropathy (CIDP)*

The recommended starting dose is 2 g/kg bw divided over 2 to 5 consecutive days followed bymaintenance 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 basedupon the patient response and maintenance response. The dosing and intervals may have to be adaptedaccording 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 after6 months, the treatment should be discontinued.

If the treatment is effective, long term treatment should be subject to the physician’s discretion basedupon the patient response. The dosing and intervals may have to be adapted according to theindividual course of the disease.

The dosage recommendations are summarised in the following table:

Indication Dose Frequency of injections

Replacement therapy

Primary immunodeficiency syndromes starting dose:(PID) 0.4 - 0.8 g/kg bwmaintenance dose: Every 3 to 4 weeks to obtain IgG0.2 - 0.8 g/kg bw trough levels of at least 6 g/l

Secondary immunodeficiencies (as 0.2 - 0.4 g/kg bw Every 3 to 4 weeks to obtain IgGdefined in 4.1) trough levels of at least 6 g/l

Immunomodulation

Primary immune thrombocytopenia (ITP) 0.8 - 1 g/kg bw on day 1, possibly repeated onceor within 3 days0.4 g/kg bw/d for 2 to 5 days

Guillain-Barré syndrome 0.4 g/kg bw/d for 5 days

Kawasaki disease 2 g/kg bw in one dose in association withacetylsalicylic acid

Chronic inflammatory demyelinating starting dose: in divided doses over 2 to 5 dayspolyneuropathy (CIDP)* 2 g/kg bwmaintenance dose: every 3 weeks over 1 to 2 days1 g/kg bw

Multifocal Motor Neuropathy (MMN) starting dose : over 2 to 5 consecutive days2 g/kg bwmaintenance dose:

1 g/kg bw every 2 to 4 weeksor or2 g/kg bw 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 oftreatment beyond 25 weeks should be subject to the physician’s discretion based upon the patientresponse and maintenance response in the long-term. The dosing and intervals may have to be adaptedaccording to the individual course of the disease.

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

No evidence is available to require a dose adjustment.

No dose adjustment unless clinically warranted, see section 4.4.

No dose adjustment unless clinically warranted, see section 4.4.

For intravenous use.

Privigen should be infused intravenously at an initial infusion rate of 0.3 ml/kg bw/hr forapproximately 30 min. If well tolerated (see section 4.4), the rate of administration may gradually beincreased 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 furthergradually 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 finalconcentration of 50 mg/ml (5%). For instruction, see section 6.6.

Hypersensitivity to the active substance (human immunoglobulins) or to any of the excipients listed insection 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.

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

Certain severe adverse reactions may be related to the rate of infusion. The recommended infusion rategiven under section 4.2 must be closely followed. Patients must be closely monitored and carefullyobserved 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 IgAdeficiency,- in patients who receive human normal immunoglobulin for the first time or, in rare cases, whenthe human normal immunoglobulin product is switched or when there has been a long intervalsince 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, patientsnaive to human normal immunoglobulin, patients switched from an alternative IVIg product orwhen there has been a long interval since the previous infusion should be monitored during thefirst infusion and for the first hour after the first infusion, in order to detect potential adversesigns. 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.).

For patients suffering from diabetes mellitus and requiring dilution of Privigen to lowerconcentrations, the presence of glucose in the recommended diluent should be taken into account.

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

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

Rarely, human normal immunoglobulin can induce a fall in blood pressure with anaphylactoidreaction, even in patients who had tolerated previous treatment with human normal immunoglobulin.

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

Haemolytic anaemia

IVIg products can contain blood group antibodies which may act as haemolysins and induce in vivocoating 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 therapydue to enhanced RBC sequestration. The Privigen manufacturing process includes an immunoaffinitychromatography (IAC) step that specifically reduces blood group A and B antibodies (isoagglutinins Aand B). Clinical data with Privigen manufactured with the IAC step show statistically significantreductions of haemolytic anaemia (see section 4.8, section 5).

Isolated cases of haemolysis-related renal dysfunction/renal failure or disseminated intravascularcoagulation and death have occurred.

The following risk factors are associated with the development of haemolysis: high doses, whethergiven as a single administration or divided over several days; non-O blood group; and underlyinginflammatory state. As this event was commonly reported in non-O blood group patients receivinghigh doses for non-PID indications, increased vigilance is recommended. Haemolysis has rarely beenreported in patients given replacement therapy for PID.

IVIg recipients should be monitored for clinical signs and symptoms of haemolysis. If signs and/orsymptoms of haemolysis develop during or after an IVIg infusion, discontinuation of the IVIgtreatment should be considered by the treating physician (see also section 4.8).

Aseptic meningitis syndrome (AMS)

Aseptic meningitis syndrome has been reported to occur in association with IVIg treatment (seesection 4.8). The syndrome usually begins within several hours to 2 days following IVIg treatment.

Symptoms may include severe headache, nuchal rigidity, drowsiness, fever, photophobia, nausea, andvomiting. Cerebrospinal fluid studies are frequently positive with pleocytosis up to several thousandcells per mm3, predominantly from the granulocytic series, and elevated protein levels up to severalhundred mg/dl.

AMS may occur more frequently in association with high-dose (2 g/kg bw) IVIg treatment and/orrapid infusion (see sections 4.2 and 4.4).

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 withoutsequelae.

Patients with a recurrence of AMS in association with IVIg treatment should be monitored for theemergence or worsening of symptoms potentially progressing to brain oedema (cerebral oedema).

Brain oedema (cerebral oedema) carries the risk of a fatal outcome.

Thromboembolism

There is clinical evidence of an association between IVIg administration and thromboembolic eventssuch as myocardial infarction, cerebral vascular accident (including stroke), pulmonary embolism anddeep vein thromboses which is assumed to be related to a relative increase in blood viscosity throughthe high influx of immunoglobulin in at-risk patients. Caution should be exercised in prescribing andinfusing IVIg in obese patients and in patients with pre-existing risk factors for thrombotic events(such as advanced age, hypertension, diabetes mellitus and a history of vascular disease or thromboticepisodes, patients with acquired or inherited thrombophilic disorders, patients with prolonged periodsof immobilisation, severely hypovolaemic patients, patients with diseases which increase bloodviscosity).

In patients at risk for thromboembolic adverse reactions, IVIg products should be administered at theminimum rate of infusion and dose practicable based on clinical judgement.

Cases of acute renal failure have been reported in patients receiving IVIg therapy. In most cases riskfactors 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 apotential increased risk for developing acute renal failure, and again at appropriate intervals.

In case of renal impairment, IVIg discontinuation should be considered. While these reports of renaldysfunction and acute renal failure have been associated with the use of many of the licensed IVIgproducts containing various excipients such as sucrose, glucose and maltose, those containing sucroseas a stabiliser accounted for a disproportionate share of the total number. In patients at risk, the use of

IVIg products that do not contain sucrose should therefore be considered. Privigen does not containsucrose, maltose or glucose.

In patients at risk of acute renal failure, IVIg products should be administered at the minimum rate ofinfusion and dose practicable based on clinical judgement.

Transfusion-related acute lung injury (TRALI)

In patients receiving IVIg, there have been some reports of acute non-cardiogenic pulmonary oedema[Transfusion Related Acute Lung Injury (TRALI)]. TRALI is characterised by severe hypoxia,dyspnoea, tachypnoea, cyanosis, fever and hypotension. Symptoms of TRALI typically developduring or within 6 hours of a transfusion, often within 1-2 hours. Therefore, IVIg recipients must bemonitored 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-unitmanagement.

Interference with serological testing

After injection of immunoglobulin, the transitory rise of the various passively transferred antibodies inthe 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 someserological tests for red cell antibodies, for example the direct antiglobulin test (DAT, direct Coombs’test).

Transmissible agents

Privigen is made from human plasma. Standard measures to prevent infections resulting from the useof medicinal products prepared from human blood or plasma include selection of donors, screening ofindividual donations and plasma pools for specific markers of infection and the inclusion of effectivemanufacturing steps for the inactivation/removal of viruses. Despite this, when medicinal productsprepared from human blood or plasma are administered, the possibility of transmitting infective agentscannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens.

The measures taken are considered effective for enveloped viruses such as human immunodeficiencyvirus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) and for the non-enveloped virusessuch as hepatitis A virus (HAV) and parvovirus B19.

There is reassuring clinical experience regarding the lack of hepatitis A or parvovirus B19transmission with immunoglobulins and it is also assumed that the antibody content makes animportant contribution to the viral safety.

This medicinal product contains less than 2.3 mg sodium per 100 ml, equivalent to 0.12% of the WHOrecommended maximum daily intake of 2 g sodium for an adult.

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

Live attenuated virus vaccines

Immunoglobulin administration may impair for a period of at least 6 weeks and up to 3 months theefficacy of live attenuated virus vaccines such as measles, rubella, mumps, and varicella. Afteradministration of this medicinal product, an interval of 3 months should elapse before vaccination withlive 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.

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

The safety of this medicinal product for use in human pregnancy has not been established in controlledclinical trials and therefore should only be given with caution to pregnant women and breast-feedingmothers. 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 ofpregnancy, 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 indirecttoxicity affecting pregnancy, embryonal or foetal development.

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

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

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 beforedriving or operating machines.

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 withintravenous administration of human immunoglobulin.

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

Cases of reversible aseptic meningitis and rare cases of transient cutaneous reactions (includingcutaneous lupus erythematosus - frequency unknown) have been observed with human normalimmunoglobulin.

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 maydevelop 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 asmyocardial infarction, stroke, pulmonary embolism and deep vein thromboses.

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 andtreated with Privigen. Another clinical study included 11 PID patients in Japan. Two ITP studies wereperformed 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 innature.

The following table shows an overview of the ADRs observed in the seven clinical studies categorizedaccording 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 asunknown.

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

MedDRA System Adverse Reaction Frequency per Frequency per

Organ Class (SOC) patient infusion

Infections and Aseptic meningitisinfestations Uncommon Rare

Blood and lymphatic Anaemia, haemolysis (includingsystem disorders haemolytic anaemia) β, leukopenia Common Uncommon

Anisocytosis (including microcytosis) Uncommon

Thrombocytosis Uncommon Rare

Decreased neutrophil count Unknown Unknown

Immune system Hypersensitivity Common Uncommondisorders Anaphylactic shock Unknown Unknown

Nervous system Headache (including sinus headache,disorders migraine, head discomfort, tension Very common Very commonheadache)

Dizziness (including vertigo) Common Uncommon

Somnolence

Tremor Uncommon Uncommon

Rare

Cardiac disorders Palpitations, tachycardia Uncommon Rare

Vascular disorders Hypertension, flushing (including hotflush, hyperaemia) Common Uncommon

Hypotension Rare

Thromboembolic events, vasculitis(including peripheral vascular Uncommon Raredisorder)

Transfusion related acute lung injury Unknown Unknown

Respiratory, Dyspnoea (including chest pain, chestthoracic and discomfort, painful respiration)mediastinal Common Uncommondisorders

Gastrointestinal Nausea, vomiting, diarrhoeadisorders Common Common

Abdominal pain Uncommon

MedDRA System Adverse Reaction Frequency per Frequency per

Organ Class (SOC) patient infusion

Hepatobiliary Hyperbilirubinaemiadisorders Common Rare

Skin and Skin disorder (including rash,subcutaneous tissue pruritus, urticaria, maculo-papular Common Commondisorders rash, erythema, skin exfoliation)

Musculoskeletal and Myalgia (including muscle spasms,connective tissue musculoskeletal stiffness, Common Uncommondisorders musculoskeletal pain)

Renal and urinary Proteinuria, increased blooddisorders creatinine Uncommon Rare

Acute renal failure Unknown Unknown

General disorders Pain (including back pain, pain inand administration extremity, arthralgia, neck pain, facialsite conditions pain) pyrexia (including chills),influenza like illness (including Very common Commonnasopharyngitis, pharyngolaryngealpain, oropharyngeal blistering, throattightness)

Fatigue Common

Asthenia (including muscular Common Uncommonweakness)

Injection site pain (including infusion Uncommon Raresite discomfort)

Investigations Decreased haemoglobin (including Common Uncommondecreased red blood cell count,decreased haematocrit), Coombs`(direct) test positive, increased alanineaminotransferase, increased aspartateaminotransferase, increased bloodlactate dehydrogenaseβ 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 identifying4 haemolytic anaemia cases after IAC versus 9,439 patients who received Privigen identifying47 haemolytic anaemia cases prior to IAC (baseline), an 89% statistically significant reduction in theoverall rate of probable haemolytic anaemia was demonstrated based on an incidence rate ratio of0.11 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 associationwith a haptoglobin, a direct antiglobulin test or indirect antiglobulin performed in the workup ofhaemolytic anaemia.

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

In Privigen clinical studies with paediatric patients, the frequency, nature and severity of adversereactions did not differ between children and adults. In post marketing reports it is observed that theproportion 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 suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

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 ofantibodies against infectious agents.

Human normal immunoglobulin contains the IgG antibodies present in the normal population. It isusually prepared from pooled plasma from not fewer than 1,000 donors. It has a distribution ofimmunoglobulin G subclasses closely proportional to that in native human plasma. Adequate doses ofthis medicinal product may restore abnormally low immunoglobulin G levels to the normal range andthus help against infections.

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

The safety and efficacy of Privigen was evaluated in 7 prospective, open-label, single-arm, multicenterstudies 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 observationalmulticentre 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 (3to 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 treatmentschedules were almost identical to each other (428.3 vs. 440.6 mg IgG/ kg bw).The PID extensionstudy 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 infusionswere 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 with2 infusions of Privigen for a total of 114 infusions. The scheduled dose of 1 g/kg bw per infusion wasclosely 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 18and 65 years were treated with Privigen at 1 g/kg bw. On day 3 patients could receive a second dose of1 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 daysafter the first infusion, which was well within the expected range. A second dose in subjects withplatelet counts ≥ 50×109/l after the first dose provided a relevant additional benefit in terms of higherand longer-lasting increases in platelet counts compared to a single dose. In subjects with plateletcounts < 50×109/l after the first dose, 30% showed a platelet response of ≥ 50×109/l after themandatory second dose.

CIDP

In the first CIDP study, a prospective multicenter open label trial (Privigen impact on mobility andautonomy PRIMA study), 28 patients (13 subjects who have previously received IVIG and 15 subjectsnot) were treated with a Privigen loading dose of 2g/kg bw given over 2-5 days followed by 6maintenance doses of 1g/kg bw over 1-2 days every three weeks. Previously treated patients werewithdrawn from IVIG until confirmed deterioration before start of Privigen. On the adjusted 10 point

INCAT (Inflammatory Neuropathy Cause and Treatment) scale a clinically meaningful improvementof 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 afterreceiving 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 patientsby 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 similarin 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% confidenceinterval [4.0, 11.7])

In a second prospective, multicenter randomized, placebo-controlled clinical study (Polyneuropathyand Treatment with Hizentra, PATH trial), 207 subjects with CIDP were treated with Privigen in theprerandomization phase of the study. Subjects all with IVIg pretreatment of at least 8 weeks and withan IVIg-dependence confirmed by clinically evident deterioration during an IVIg withdrawal phase ofup to 12 weeks, received a Privigen loading dose of 2 g/kg bw followed by up to 4 Privigenmaintenance 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 primarilydefined by a decrease of ≥ 1 point at the adjusted INCAT score. Additional measures of CIDPimprovement were an increase in R-ODS (Rasch-built Overall Disability Scale) score of ≥ 4 points, amean grip strength increase of ≥ 8 kPa, or an MRC sum score increase of ≥ 3 points. Overall, 91 % ofsubjects (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), with149 patients responding already by week 10. A total of 43 of the 207 patients achieved a better CIDPstatus 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 pointsin 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 PRIMAwas 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 and6.1 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 and10.8 kPa in IVIg pretreated subjects) in the PRIMA study, while in PATH the grip strength of thedominant hand improved by 12.2 kPa. For the non dominant hand similar results were observed inboth PRIMA and PATH trials.

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

Post-Authorisation Safety Study (PASS)

In an observational hospital-based cohort Post-Authorisation Safety Study (PASS), the risk ofhaemolytic anaemia following Privigen therapy was evaluated in patients with various immunologicalconditions 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 ofhaemolytic anaemia were defined by an ICD-9 or ICD-10 hospital discharge code specific forhaemolytic anaemia. (Possible cases of haemolytic anaemia consisted of an unspecified transfusionreaction identified via ICD-9 or ICD-10 discharge codes or via review of hospital charge descriptionsin temporal association with a haptoglobin, a direct antiglobulin test or indirect antiglobulin performedin the workup of haemolytic anaemia).

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

Baseline IAC

Periodɸ 1. January 2008- 1. October 2016-31. December 2012 30. April 2019

Median anti-A titers£ 1:32 1:8

Median anti-B titers£ 1:16 1:4

Probable haemolytic anaemiaα cases 47 4

Patient number (n) n=9439 n=7759

Crude incidence rate of probable haemolytic 0.74 0.08anaemia α per 10.000 patient-days at risk 95% CI&: 0.54-0.98 95% CI: 0.02-0.20

Incidence rate reduction of probable - 89%haemolytic anaemia α versus baseline

Adjustedꝣ incidence rate ratio for haemolytic - 0.11anaemia versus baseline 95% CI: 0.04-0.31,one-sided p-value: <0.01ɸ The exclusion of human blood plasma donors with high anti-A titres performed between 1. October 2013 and31. December 2015 as the initial risk minimisation measure for haemolytic anaemia indicated a 38% reduction in probablehaemolytic anaemia incidence versus baseline and was subsequently replaced by the IAC step in the Privigen manufacturingprocess, as provided above.£ Median isoagglutinin titers measured by direct testing method according to Ph.Eurα Probable haemolytic anaemia case: defined by an ICD-9 or ICD-10 hospital discharge code specific for haemolytic anaemiaand the occurrence during the time interval from the first infusion up to 30 days after the last infusion, if >1 Privigeninfusions were administered.& Confidence intervalꝣ 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 versusbaseline 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 entirestudy period from 1 January 2008 to 30 April 2019. No paediatric patients with CIDP given a total of486 Privigen administrations experienced haemolytic anaemia, AMS, acute renal failure, severeanaphylactic reaction or a thromboembolic event. Two patients experienced a moderate anaphylacticreaction, equating to 0.4% of all Privigen administrations.

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

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

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

IgG and IgG complexes are broken down in the cells of the reticuloendothelial system. The half-lifemay vary from patient to patient. The pharmacokinetic parameters for Privigen were determined in aclinical study in PID patients (see section 5.1). 25 patients (aged 13-69 years) participated in thepharmacokinetic (PK) assessment. In this study, the median half-life of Privigen in PID patients was36.6 days. In an extension of this study, 13 PID patients (aged 3-65 years) participated in a PK sub-study. 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) Extension Study (N=13)

ZLB03_002CR ZLB05_006CR

Median (Range) Median (Range)

Cmax (peak, g/l) 23.4 (10.4-34.6) 26.3 (20.9-32.9)

Cmin (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)t½ (days) 36.6 (20.6-96.6) 31.1 (14.6-43.6)

Cmax, maximum serum concentration; Cmin, trough (minimum level) serum concentration; t½,elimination half-life

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

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

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

L-proline

Water for injections

Hydrochloric acid (for pH-adjustment)

Sodium hydroxide (for pH adjustment)

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

3 years

Stability after first opening:

Once the vial has been broached, its contents should be used promptly. Because the solution containsno 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 isrecommended. The in-use stability of Privigen after dilution with a 5% glucose solution to a finalconcentration of 50 mg/ml (5%) has been demonstrated for 10 days at 30°C; however, the microbialcontamination aspect was not studied.

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.

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 sizes1 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.

Privigen comes as a ready-to-use solution in single-use vials. The product should be brought to roomtemperature (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 arecloudy or have deposits should not be used.

If dilution is desired, 5% glucose solution should be used. For obtaining an immunoglobulin solutionof 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 localrequirements.

CSL Behring GmbH

Emil-von-Behring-Strasse 76

D-35041 Marburg

Germany

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

Date of first authorisation: 25 April 2008

Date of latest renewal: 28 November 2017

Detailed information on this medicinal product is available on the website of the European Medicines

Agency: http://www.ema.europa.eu