4.1. 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 level of <4 g/l.

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

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

• Primary immune thrombocytopenia (ITP), in patients at high risk of bleeding or prior to surgery to correct the platelet count.

• Guillain-Barré syndrome.

• Kawasaki disease (in conjunction with acetylsalicylic acid; see 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 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. 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 section 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-Barré 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 physician's discretion based upon the patient response and maintenance response. The dosing and intervals may have to be adapted according to the individual course of the disease.

Multifocal motor neuropathy (MMN)

Starting dose: 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 section 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-Barré 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 2-5 days

every 3 weeks over 1-2 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 4.8ml/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.).

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

Hypersensitivity

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 only abnormality of concern.

Rarely, human normal immunoglobulin can induce a fall in blood pressure with anaphylactoid reaction, 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 vivo coating of red blood cells (RBC) with immunoglobulin, causing a positive direct antiglobulin reaction (Coombs' test) and, rarely, haemolysis. Haemolytic anaemia can develop subsequent to IVIg therapy due to enhanced RBC sequestration.

The Privigen manufacturing process includes an immunoaffinity chromatography (IAC) step that specifically reduces blood group A and B antibodies (isoagglutinins A and B).

Clinical data with Privigen manufactured with the IAC step show statistically significant reductions of haemolytic anaemia (see section 4.8, section 5).

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

The following risk factors are associated with the development of haemolysis: high doses, whether given as a single administration or divided over several days; non-0 blood group; and underlying inflammatory state. As this event was commonly reported in non-0 blood group patients receiving high doses for non-PID indications, increased vigilance is recommended.

Haemolysis has rarely been reported in patients given replacement therapy for PID.

IVIg recipients should be monitored for clinical signs and symptoms of haemolysis. If signs and/or symptoms of haemolysis develop during or after an IVIg infusion, discontinuation of the IVIg treatment 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 (see section 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, and vomiting. Cerebrospinal fluid studies are frequently positive with pleocytosis up to several thousand cells per mm3, predominantly from the granulocytic series, and elevated protein levels up to several hundred mg/dl.

AMS may occur more frequently in association with high-dose (2 g/kg bw) IVIg treatment and/or rapid 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 without sequelae.

Patients with a recurrence of AMS in association with IVIg treatment should be monitored for the emergence 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 events such as myocardial infarction, cerebral vascular accident (including stroke), pulmonary embolism and deep vein thromboses which is assumed to be related to a relative increase in blood viscosity through the high influx of immunoglobulin in at-risk patients. Caution should be exercised in prescribing and infusing IVIg in obese patients and in patients with pre-existing risk factors for thrombotic events (such as advanced age, hypertension, diabetes mellitus and a history of vascular disease or thrombotic episodes, patients with acquired or inherited thrombophilic disorders, patients with prolonged periods of immobilisation, severely hypovolaemic patients, patients with diseases which increase blood viscosity).

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

Acute renal failure

Cases of acute renal failure have been reported in patients receiving IVIg therapy.

In most cases risk factors have been identified, such as pre-existing renal insufficiency, diabetes mellitus, hypovolaemia, overweight, concomitant nephrotoxic medicinal products or age over 65.

Renal parameters should be assessed prior to infusion of IVIg, particularly in patients judged to have a potential increased risk for developing acute renal failure, and again at appropriate intervals.

In case of renal impairment, IVIg discontinuation should be considered. While these reports of renal dysfunction and acute renal failure have been associated with the use of many of the licensed IVIg products containing various excipients such as sucrose, glucose and maltose, those containing sucrose as a stabiliser accounted for a disproportionate share of the total number. In patients at risk, the use of IVIg products that do not contain sucrose should therefore be considered. Privigen does not contain sucrose, maltose or glucose.

In patients at risk of acute renal failure, IVIg products should be administered at the minimum rate of infusion 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 develop during or within 6 hours of a transfusion, often within 1-2 hours. Therefore, IVIg recipients must be monitored for and IVIg infusion must be immediately stopped in case of pulmonary adverse reactions. TRALI is a potentially life-threatening condition requiring immediate intensive-care-unit management.

Interference with serological testing

After injection of immunoglobulin the transitory rise of the various passively transferred antibodies in the patient's blood may result in misleading positive results in serological testing.

Passive transmission of antibodies to erythrocyte antigens, e.g. A, B, D, may interfere with some serological tests for red cell antibodies for example the direct antiglobulin test (DAT, direct Coombs' test).

Transmissible agents

Privigen is made from human plasma. Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation/removal of viruses. Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infective agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens.

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

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

Sodium content

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

Paediatric population

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

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, categorised according to the MedDRA System Organ Class (SOC), Preferred Term Level (PT) and frequency.

Frequencies were evaluated using 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 categorised 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

Blood and lymphatic system disorders

Anaemia, haemolysis (including haemolytic anaemia)β, 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 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' (direct) test positive, increased alanine aminotransferase, increased aspartate aminotransferase, increased blood lactate dehydrogenase

Common

Uncommon

βThe 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 authorization 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 UK Yellow Card Scheme.

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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.