Replacement therapy in adults and children in:

·    Primary immunodeficiency syndromes such as:

-       congenital agammaglobulinaemia and hypogammaglobulinaemia

-       common variable immunodeficiency

-       severe combined immunodeficiency and Wiskott-Aldrich syndrome

-       IgG subclass deficiencies with recurrent infections

·    Myeloma or chronic lymphocytic leukaemia with severe secondary hypogammaglobulinaemia and recurrent infections.

Immunomodulatory therapy:

·    Hizentra is indicated for the treatment of patients with chronic inflammatory demyelinating

polyneuropathy (CIDP) as maintenance therapy after stabilization with intravenously administered immunoglobulins (IVIg).

Posology

The dose and the dosage regimen depend on the indication.

The therapy should be initiated and monitored under the supervision of a healthcare professional experienced in the IgG treatment of immunodeficiency or CIDP.

Replacement therapy in adults and children

The dose may need to be individualised for each patient dependent on the clinical response and serum IgG trough levels. The following dose regimens are given as a guideline:

The dose regimen using the subcutaneous route should achieve a sustained level of IgG. A loading dose of at least 0.2 – 0.5 g/kg (1.0 – 2.5 mL/kg) body weight is required. This may need to be divided over several days. After steady-state IgG levels have been attained, maintenance doses are divided into smaller doses and administered at repeated intervals to reach a cumulative monthly dose in the order of 0.4 – 0.8 g/kg (2.0 – 4.0 mL/kg) body weight (see section “Pharmacokinetics”).

For patients switching from intravenous treatment to subcutaneous therapy, the monthly dose is divided into smaller doses and administered at repeated intervals (see section “Pharmacokinetics”).

Trough levels should be measured and assessed in conjunction with the patient’s clinical response. Depending on the clinical response (e.g. infection rate), adjustment of the dose and/or the dose interval should be considered in order to aim for higher trough levels.

Immunomodulatory therapy in CIDP

The therapy with Hizentra is initiated 1 week after the last IVIg infusion. The recommended initial subcutaneous dose is 0.4 g/kg body weight per week. If a patient is clinically stable, the Hizentra weekly dose may be reduced to a minimum of 0.2 g/kg body weight per week.

In the event of a relapse when decreasing the subcutaneous dose to 0.2 g/kg body weight per week a return should be made to the higher subcutaneous dose of 0.4 g/kg body weight per week. If the patient does not improve or relapses on the higher dose a switch should be made to IVIg, initiating with the loading dose. In the event of a rescue treatment with IVIg once, resumption of SCIg cannot be recommended.

The weekly dose may be divided into smaller doses and administered at the desired frequency. When administered every two weeks, the dose of Hizentra must be doubled.

Hizentra has been shown to be superior to placebo after switching from intravenous immunoglobulins (IVIg). Direct comparative data for Hizentra versus IVIg are not available.

Posology for children and adolescents

The posology is determined on the basis of body weight as in adults and adjusted to the clinical outcome of the substitution therapy. Hizentra was evaluated in 54 children aged 2 to 12 years and 45 adolescents aged between 12 and <18 years with PID. No paediatric-specific dose requirements were necessary to achieve the desired serum IgG levels.

Hizentra therapy in paediatric CIDP patients has not been evaluated in clinical studies.

Elderly patients

As the dose is administered on the basis of body weight and adjusted to the clinical outcome, it is not expected that the dose in elderly patients should differ from that in subjects aged 18 to 65 years.

Hizentra was investigated in clinical studies in 9 PID patients aged >65 years. No specific dose adjustments were necessary to achieve the desired serum IgG levels.

Hizentra was investigated in clinical studies in 61 CIDP patients aged >65 years. No specific dose adjustments were necessary to achieve the desired clinical outcome.

Method of administration

Hizentra must be administered via the subcutaneous route only.

Infusion for home treatment should be commenced and initially supervised and monitored by a healthcare professional. The healthcare professional should already be experienced in supervising the home treatment of patients with primary immunodeficiency syndromes. The patient or the caregiver must be instructed in using an infusion pump, infusion techniques, how to keep a treatment diary and identifying severe adverse reactions and measures to be taken should such reactions occur.

Hizentra may be injected into sites such as the abdomen, thigh, upper arm and lateral hip (see figure 1). If large doses are given (> 25 mL for replacement therapy or > 50 mL for CIDP) it is advisable to administer them at multiple sites. In infants and children, the infusion site should be changed after every 5-15 mL. There is no limit to the number of infusion sites. Infusion sites should be at least 5 cm apart. Several infusion sets can be used simultaneously. The volume of injected product at a given site may vary.

Figure 1: Possible infusion sites for Hizentra

Infusion Rate

Replacement Therapy

The recommended initial infusion rate depends on the individual needs of the patient and should not exceed 15 mL/hour/site. If well tolerated, the infusion rate may then be gradually increased up to

25 mL/hour/site.

Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)

The recommended initial infusion rate depends on the individual needs of the patient and should not exceed 20 mL/hour/site. If well tolerated, the infusion rate may then be gradually increased up to

50 mL/hour/site.

When administered every two weeks, the required Hizentra volume can be delivered if necessary in up to 4 sessions, e.g. once in the morning and once in the evening on 2 consecutive days or any other days of the second week.

If Hizentra is accidentally administered into a blood vessel, patients may go into shock.

The recommended infusion rate given under section “Posology/method of administration: Infusion rate” should be adhered to. Patients should be closely monitored during their first supervised infusions for any adverse events during the infusion period and for at least 20 minutes thereafter.

Certain adverse reactions may occur more frequently in patients who receive human immunoglobulin for the first time or, in rare cases, when the human immunoglobulin product has been switched or treatment stopped for more than eight weeks.

Hypersensitivity/anaphylactic reactions

True allergic reactions are rare. They can occur in patients with anti-IgA antibodies. Patients with anti- IgA antibodies, in whom treatment with subcutaneous IgG products remains the only option, should be switched to Hizentra only under close medical supervision.

Rarely, the administration of human immunoglobulin can induce a sudden fall in blood pressure with an anaphylactic reaction, even in patients who have tolerated previous treatment with human immunoglobulin.

Potential complications can often be avoided by ensuring that patients:

-              are not sensitive to human immunoglobulin, by initially injecting the product slowly (≤ 15 mL/hour/site);

-              are carefully monitored for any symptoms throughout the infusion period and for at least 20 minutes after administration. In particular, patients naive to human immunoglobulin, patients switched from another immunoglobulin preparation or patients who have not been treated for a long interval since the previous infusion should be monitored during the first infusion and for the first hour thereafter in order to detect potential adverse signs.

If there is any suspicion of allergic or anaphylactic type reactions the infusion must be immediately discontinued. In the event of shock, standard medical treatment should be administered.

Embolic and thromboembolic events

There is clinical evidence of an association between the immunoglobulin administration and embolic/thromboembolic events such as myocardial infarction, stroke, deep venous thrombosis and pulmonary embolism. Particular caution should be therefore exercised in patients with pre-existing risk factors for thrombotic events (e.g. advanced age, hypertension, diabetes mellitus, history of vascular disease or thrombotic episodes, acquired or inherited thrombophilic disorders, prolonged

periods of immobilization, severe hypovolaemia, and diseases which increase blood viscosity). Patients should be informed about first symptoms of thromboembolic events such as shortness of breath, pain and swelling of limbs, focal neurological deficits and chest pain and should be advised to contact their physician immediately upon onset of symptoms. Patients should be sufficiently hydrated before use of immunoglobulins.

Aseptic Meningitis Syndrome (AMS)

AMS cases have occurred with use of intravenous or subcutaneous immunoglobulin. The syndrome usually begins within several hours to 2 days following immunoglobulin treatment. AMS is characterised by the following signs and symptoms: severe headache, neck stiffness, drowsiness, fever, photophobia, nausea and vomiting. Patients exhibiting signs and symptoms of AMS should receive a thorough neurological examination, including CSF tests, to rule out other causes of meningitis. Discontinuation of immunoglobulin treatment results in remission of AMS within several days without sequelae.

Renal complications

Cases of severe adverse reactions affecting the kidneys have been reported in patients receiving immunoglobulin therapy, in particular with preparations containing sucrose (Hizentra does not contain any sucrose). These reactions include acute renal failure, acute tubular necrosis, proximal tubulopathy and osmotic nephrosis. Factors which increase the risk of renal complications include, among others, existing renal insufficiency, diabetes mellitus, hypovolaemia, nephrotoxic co-medications, age over 65, sepsis, hyperviscosity and paraproteinaemia.

Haemolytic anaemia

Immunoglobulin products can contain blood group antibodies that may act as haemolysins and induce in vivo coating of red blood cells with immunoglobulin. This may cause a positive direct antiglobulin reaction (DAT, direct Coombs test) and, rarely, haemolysis. Delayed haemolytic anaemia can develop subsequent to IgG therapy due to enhanced RBC sequestration. Haemolytic anaemia has been reported.

Information on safety with respect to transmissible agents

Hizentra 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 (see section “Properties/Effects”).

Nevertheless, 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 the human immunodeficiency virus (HIV), the hepatitis B virus (HBV) and the hepatitis C virus (HCV), and for the non-enveloped viruses such as the hepatitis A virus (HAV) and parvovirus B19.

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

It is recommended that whenever Hizentra is administered to a patient the name and batch number of the medicinal product are recorded in order to maintain a link between the patient and medicinal product batch.

Hizentra contains less than 1 mmol of sodium (23 mg) per pre-filled syringe; that is to say, it is almost “free of sodium”.

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, mumps, rubella 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 vaccine, this impairment may persist for up to 1 year. Patients receiving measles vaccine should therefore have their antibody status checked.

No data from prospective clinical trials on the use of Hizentra in pregnant women and breast-feeding women is available. Hizentra should therefore only be given with caution to pregnant women and breast-feeding mothers. Long-term clinical experience with immunoglobulins suggests however that no harmful effects on the course of pregnancy, or on the foetus or neonate are to be expected.

Continued treatment of the pregnant woman is important to ensure that the neonate is born with appropriate passive immunity.

Immunoglobulins are excreted into breast milk and may contribute to the transfer of protective antibodies to the neonate.

The ability to drive and operate machines may be impaired by some adverse reactions associated with Hizentra. Patients who experience adverse reactions during treatment should wait for these to resolve before driving or operating machines.

Summary of the safety profile

Adverse drug reactions (ADR) such as chills, headache, fever, vomiting, allergic reactions, nausea, arthralgia, low blood pressure and moderate back pain may occur occasionally in association with human immunoglobulin medication.

Rarely human 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.

Local reactions at infusion sites: swelling, soreness, redness, induration, local heat, itching, bruising and rash.

Adverse drug reactions (ADRs) collected from clinical trials and post marketing observations with Hizentra:

In seven phase III studies in patients with primary immunodeficiency (n = 231) and two phase III studies with CIDP patients (n = 197) with Hizentra, (total n = 428) the following ADRs were reported and are summarised and categorised below according to the MedDRA System Organ Class and frequency.

Frequencies per patient have been evaluated using the following criteria: very common (³1/10), common (³1/100 to <1/10), uncommon (³1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000) and very rare (<1/10,000). The frequency of spontaneous ADRs after its marketing launch is reported as isolated cases.

Infections and infestations

Very common: Nasopharyngitis (20.3%)

Blood and lymphatic system disorders:

Uncommon:       Blood lactate dehydrogenase increased Isolated cases: Haemolytic anaemia**

Immune system disorders:

Uncommon:       Hypersensitivity Isolated cases: Anaphylactic reactions

Nervous system disorders:

Very common: Headache (including migraine) (14.0%) Common:  Dizziness

Uncommon:       Aseptic meningitis syndrome (AMS)*, tremor (including psychomotor hyperactivity) Isolated cases: Burning sensation, somnolence

Cardiac disorders:

Uncommon:       Tachycardia (including blood pressure increase)

Vascular disorders:

Common:           Hypertension

Uncommon:       Hot flushes, aldolase increase

Isolated cases: Embolic- and thromboembolic events (including thrombosis, embolism, transient ischaemic attack, hemiparesis, transient blindness, haemorrhagic cerebral infarction, hemiplegia)

Respiratory, thoracic and mediastinal disorders:

Common:           Cough

Gastrointestinal disorders:

Common:          Diarrhoea, abdominal pain, nausea, vomiting

Skin and subcutaneous tissue disorders:

Very common: Rash (including erythema) (10.7%) Common:                              Pruritus, urticarial, contact dermatitis

Musculoskeletal, connective tissue and bone disorders:

Very common: Musculoskeletal pain (including muscle spasm and muscular weakness) (11.4%) Common:                              Arthralgia

Uncommon:       Arthritis

Uncommon: Serum creatine phosphokinase increased

Renal and urinary disorders:

Uncommon:       Haematuria, raised creatinine

Isolated cases: Acute renal failure**, acute tubular necrosis**, proximal   tubulopathy** und osmotic nephrosis **

General disorders and administration site conditions:

Very common: Local reactions at the infusion site, (including bruising and haematoma) (43.9%) Common:     Fever (including body temperature increase), tiredness (including general malaise),

chest pain, flu-like illness, pains Uncommon:           Chills (including hypothermia), weight loss Isolated cases: Ulcer at the infusion site

*Aseptic Meningitis Syndrome (ASM) symptoms include: stiff neck, headache, pyrexia, photophobia, nausea, and vomiting.

**Adverse immunoglobulin class effects.

Information on virus safety: see chapter “Warnings and Precautions”.

Reporting of 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 new or suspected adverse reactions.

To reports any side effect(s):

Saudi Arabia:

·   The National Pharmacovigilance Centre (NPC):

-       SFDA Call Center: 19999

-       E-mail: npc.drug@sfda.gov.sa

-       Website: https://ade.sfda.gov.sa

Other GCC States:

Please contact the relevant competent authority.

Consequences of an overdose are not known.

ATC code: J06BA01

Pharmacotherapeutic group: immune sera and immunoglobulins: immunoglobulins, normal human, for extravascular administration.

1.1   Mechanism of action/pharmacodynamics

Hizentra contains a broad spectrum of opsonising and neutralising IgG antibodies against a large number of bacterial and viral pathogens.

Hizentra contains the immunoglobulin G antibodies present in the average population. It is prepared from plasma from not less than 1000 donors. The IgG subclass distribution roughly equals that of unprocessed human plasma.

Sufficient Hizentra doses can raise low IgG antibody levels to normal levels and thus help to combat infections.

The mechanism of action of Hizentra in patients with CIDP is not fully understood, but may include immunomodulatory effects.

Clinical efficacy

Primary Immunodeficiency Syndromes

The safety and efficacy of Hizentra in patients with primary immunodeficiency syndromes has been assessed in four prospective open-label, single-arm and multicentre studies in Europe and the US. In the European pivotal study, a total of 51 subjects with primary immunodeficiency syndromes aged between 3 and 60 years old were treated with Hizentra for up to 41 weeks. The mean dose administered each week was 119 mg/kg body weight. Sustained IgG trough levels with mean concentrations of 7.99 – 8.25 g/L were thereby achieved throughout the treatment period. Subjects received in total 1831 weekly Hizentra infusions.

In the subsequent extension study a total of 40 patients treated previously in the pivotal study (age 4 - 52 years) were enrolled and treated for up to 46 months at the same dose. Patients received a total of 5405 weekly Hizentra infusions.

Over the entire treatment period constant IgG trough levels were achieved with average concentrations of 7.5 – 8.5 g/L, thus confirming the results of the pivotal study. The rate of acute serious bacterial infections (aSBI) was 0.0478 per patient per year, with an upper 99% confidence interval (CI) of 0.1252.

In the US study, a total of 49 subjects with primary immunodeficiency syndromes aged between 5 and 72 years old were treated with Hizentra for up to 15 months. The mean dose administered each week was 228 mg/kg body weight. Sustained IgG trough levels with a mean concentration of 12.53 g/L were thereby achieved throughout the treatment period. Subjects received in total 2264 weekly Hizentra infusions.

In the subsequent US extension study, a total of 21 previously treated patients (aged 5 - 69 years) were enrolled and treated for up to 87 weeks at the same dose. Patients received a total of 1735 weekly Hizentra infusions.

Over the entire treatment period constant IgG trough levels were achieved with average concentrations of 11.71 – 12.76 g/L (overall average 11.98 g/L), thus confirming the results of the pivotal study. IgG trough levels never fell below 5 g/L during administration in any of the treated patients. The aSBI rate was 0.06 per patient per year, with an upper 99% confidence interval of 0.257.

Children and adolescents

The safety and efficacy of Hizentra has been examined in paediatric patients aged between 2 and 18 years.

Hizentra was evaluated in 54 paediatric PID patients aged 2 to <12 years in 45 paediatric patients aged 12 to <18 years.

No differences were established between adult and paediatric patients in terms of pharmacokinetic parameters, safety or efficacy. In paediatric patients, no specific dose was necessary in order to achieve the desired serum IgG levels.

Elderly patients

With regard to safety and efficacy, no differences were observed overall between PID patients older than 65 years and PID patients aged 18 to 65 years. In the clinical studies, Hizentra was investigated in 9 PID patients older than 65 years.

Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)

The safety, efficacy and tolerability of Hizentra in patients with CIDP was evaluated in a multicentre, double-blind, randomised, placebo-controlled, parallel-group phase III study - PATH [Polyneuropathy and Treatment with Hizentra]. 172 previously IVIg-treated subjects were randomized into groups receiving weekly doses of 0.2 g/kg body weight of Hizentra, 0.4 g/kg body weight of Hizentra or placebo and subsequently treated for 24 weeks. The average duration of exposure was 118.9 days in the 0.2 g/kg body weight group and 129 days in the 0.4 g/kg body weight group (maximum exposure in each group up to 167 days and 166 days, respectively). The study participants generally used 4 infusion sites simultaneously (up to 8 sites at a time).

A total of 57 study participants received 1514 infusions in the placebo group, 57 study participants received 2007 infusions in the Hizentra group at 0.2 g/kg body weight, and 58 study participants received 2218 infusions in the Hizentra group at 0.4 g/kg body weight (a total of 5739 infusions).

The primary efficacy endpoint was the percentage of subjects who had CIDP recurrence (defined as an increase of ≥ 1 point on the adjusted Inflammatory Neuropathy Cause and Treatment (INCAT) scale versus the baseline) or who, for some other reason, were removed from the Hizentra treatment phase. Both Hizentra doses were superior to placebo for the primary efficacy endpoint.

A statistically significantly lower percentage of Hizentra-treated patients had recurrent CIDP or were withdrawn from the study for other reasons: 32.8% for 0.4 g/kg body weight and 38.6% for 0.2 g/kg body weight compared to 63.2% of placebo-treated subjects [p <0.001 and p = 0.007 respectively]. When recurrent cases were considered in isolation, CIDP recurrence rates were 19.0% for Hizentra at

0.4 g/kg body weight and 33.3% for 0.2 g/kg body weight Hizentra versus 56.1% for placebo

(p < 0.001 and p = 0.012 respectively). Over a treatment period of up to 24 weeks, Hizentra thus prevented recurrence in 81% and 67% of study participants in the 0.4 g/kg body weight and 02 g/kg body weight groups respectively. In the placebo group, no recurrence occurred in 44% of the study participants.

The time to CIDP recurrence was evaluated and corresponding probabilities for CIDP recurrence based on Kaplan-Meier estimates were: placebo 58.8%; 0.2/kg body weight Hizentra 35.0% and 0.4 g

/ kg body weight Hizentra 22.4%. The hazard ratios (95% CI) for the lower and higher dose compared to placebo were 0.48 (0.27; 0.85) and 0.25 (0.12; 0.49), respectively. The observed difference between the 0.2 g/kg body weight Hizentra group and the 0.4 g/kg body weight Hizentra group did not attain statistical significance.

Study participants remained stable in the efficacy outcomes (INCAT scale, average grip and mean Medical Research Council (MRC) scale) in both Hizentra dosing groups compared to study participants in the placebo group, whose outcomes worsened. Study participants in the high-dose Hizentra group remained stable on Rasch's percentile Overall Disability Scale (R-ODS).

Electrophysiological parameters remained stable for study participants in both Hizentra dose groups.

82 CIDP patients from the PATH study were included in the multicentre, 48-week, open-label phase III extension study. In the extension study, the long-term safety and efficacy of Hizentra maintenance therapy with two different weekly doses of 0.2 g/kg or 0.4 g/kg body weight was investigated. As a result of the study design, the same patient was able to receive both doses during the study, 72 patients received a dose of 0.4 g/kg body weight and 73 patients received a dose of 0.2 g/kg. The mean duration of the treatment was 125.8 days (range: 1-330) in the group with 0.2 g/kg body weight and

196.1 days (range 1-330) in the group with 0.4 g/kg body weight.

Patients who had completed the pivotal PATH study without a recurrence with a dose of 0.4 g/kg body weight and initially received this dose in the extension study had a rate of recurrence of 5.6% (1 out of 18 patients).

Of all patients who had received 0.4 g/kg body weight in the PATH extension study, 9.7% (7 out of 72 patients) experienced a recurrence.

The patients who had completed the PATH study without a recurrence with 0.2 g/kg body weight and initially received this dose in the extension study had a rate of recurrence of 50% (3 out of 6 patients). Of all patients who received 0.2 g/kg body weight in the extension study, 47.9% (35 out of 73 patients) experienced a recurrence. The reduction in the dose from 0.4 g/kg body weight to 0.2 g/kg body weight in the extension study without a recurrence was possible in 67.9% of patients (19 out of 28 patients). All patients who experienced a recurrence recovered within 4 weeks of treatment with

0.4 g/kg body weight.

Grip strength, the total number of points on the MRC Scale and the R-ODS centile score remained stable compared with baseline in patients who did not experience a recurrence in the extension study.

Children and adolescents

Treatment of paediatric CIDP patients with Hizentra has not been evaluated in clinical studies.

Elderly patients

There were no overall differences in safety and efficacy between patients older than 65 years and patients aged 18 to 65 years. In the clinical studies with CIDP patients, 61 people older than 65 years were treated with Hizentra.

Following subcutaneous administration of Hizentra, peak IgG serum levels are achieved after approximately 2 days.

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

Primary Immunodeficiency Syndromes

Simulations with population-pharmacokinetic models suggest that a comparable IgG exposure (Cmax, AUC0-14days, Cmin, 14 days) is achieved when the double weekly Hizentra dose is administered every two weeks. These simulations further suggest that a comparable IgG exposure is achieved when the weekly maintenance dose of Hizentra is divided in several doses (e.g. 2, 3 or 5 times per week or daily).

If 2-3 daily doses are missed during continuous daily dosing, simulations suggest that this results in a mean serum IgG level decrease of about ≤ 4% compared to consistent daily dosing. By subsequent administration of the missed doses at the first day in addition to the daily dose, when daily dosing is resumed, the median IgG concentration profile recovers within 2 - 3 days. However, if the missed doses are not replaced when dosing is resumed, steady-state IgG trough levels are only attained after a treatment time of up to 5-6 weeks.

Children and adolescents

No differences in pharmacokinetic parameters have been established between adult and paediatric PID subjects.

Elderly patients

Overall, no differences in the pharmacokinetic parameters of PID patients aged >65 years and aged 18 to 65 years have been observed.

Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)

In the PATH study, study participants (n = 172) achieved sustained trough values over a period of 24 weeks when receiving weekly doses of 0.2 g/kg body weight or 0.4 g / kg body weight. The mean (SD) IgG-trough concentrations after a Hizentra treatment were 20.4 (3.24) g/L in the group receiving

0.4 g/kg body weight and 15.4 (3.06) g/L in the group receiving 0.2 g/kg body weight. Simulations with population-pharmacokinetic models in the PATH Study suggest that a comparable IgG exposure (Cmax, AUC0-14 days, Cmin, 14 days) is achieved if the CIDP study participants are given double the Hizentra dose every two weeks. These simulations lead to the further assumption that a comparable IgG exposure can be similarly achieved in the CIDP patient population if the weekly maintenance dose of Hizentra is divided into several, more frequent doses (2 - 7 times a week).

Children and adolescents

Treatment of paediatric CIDP patients below 18 years with Hizentra has not been evaluated in clinical studies.

Elderly patients

Overall, no differences in the pharmacokinetic parameters were observed between CIDP patients aged

>65 years and aged 18 to 65 years.

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

The safety of Hizentra has been assessed in several preclinical studies, with particular reference to the excipient L-proline. Preclinical data revealed no special risk for humans based on safety pharmacology and toxicity studies.

Please see section 2 b.

This medicinal product must not be mixed with other medicinal products.

Interference with diagnostic methods

After immunoglobulin infusion the transient rise in various passively transferred antibodies in the patient's blood may result in false positive results on serological testing.

Passive transmission of antibodies against erythrocyte antigens, e.g. A, B and D, may interfere with some serological tests for red cell allo-antibodies (e.g. Coombs test), reticulocyte counts and haptoglobin tests.

Interactions with live attenuated vaccines: see section “Interactions“.

Do not store above 25 C. Do not freeze. Keep out of the reach and sight of children.

Keep the blistered pre-filled syringe in the outer carton in order to protect from light.

Shelf life after opening the package:

Hizentra is intended for single-use only. Because the solution contains no preservative, Hizentra should be administered as soon as possible after opening the pre-filled syringe.

5, 10, 20 or 50 ml of solution in a pre-filled syringe (cyclo-olefin-copolymer (COC)) with mounted bromobutyl tipcap and closed with a bromobutyl plunger.

Pack sizes

1 x 5 ml (1g) pre-filled syringe 1 x 10 ml (2g) pre-filled syringe 1 x 20 ml (4g) pre-filled syringe

Not all pack sizes may be marketed

Hizentra is provided as a ready-to-use solution in single-use pre-filled syringes. The medicinal product should be at room or body temperature before use.

The solution should be clear and pale-yellow or light-brown. Do not use if the solution is cloudy or has particulate matter.

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