HIZENTRA 200mg / ml subcutaneous injection solution medication leaflet

Hizentra 200 mg/ml solution for subcutaneous injection

Hizentra 200 mg/ml solution for subcutaneous injection in pre-filled syringe

Human normal immunoglobulin (SCIg)

One ml contains:

Human normal immunoglobulin ................................................................................................... 200 mg(purity: at least 98% is immunoglobulin type G (IgG))

Vials

Each vial of 5 ml solution contains: 1 g of human normal immunoglobulin

Each vial of 10 ml solution contains: 2 g of human normal immunoglobulin

Each vial of 20 ml solution contains: 4 g of human normal immunoglobulin

Each vial of 50 ml solution contains: 10 g of human normal immunoglobulin

Pre-filled syringes

Each pre-filled syringe of 5 ml solution contains: 1 g human normal immunoglobulin

Each pre-filled syringe of 10 ml solution contains: 2 g human normal immunoglobulin

Each pre-filled syringe of 20 ml solution contains: 4 g human normal immunoglobulin

Each pre-filled syringe of 50 ml solution contains: 10 g human normal immunoglobulin

Distribution of the IgG subclasses (approx. values):

IgG1 ............ 69%

IgG2 ............ 26%

IgG3 ............ 3%

IgG4 ............ 2%

The maximum IgA content is 50 micrograms/ml.

Produced from the plasma of human donors.

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

For the full list of excipients, see section 6.1.

Solution for subcutaneous injection.

The solution is clear and pale-yellow or light-brown.

Hizentra has an approximate osmolality of 380 mOsmol/kg.

Replacement therapy in adults, children and adolescents (0-18 years) in:− Primary immunodeficiency syndromes 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)* 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.

Immunomodulatory therapy in adults, children and adolescents (0-18 years):− Hizentra is indicated for the treatment of patients with chronic inflammatory demyelinatingpolyneuropathy (CIDP) as maintenance therapy after stabilization with IVIg.

The dose and dose regimen are dependent on the indication.

Therapy should be initiated and monitored under the supervision of a healthcare professionalexperienced in the treatment of immunodeficiency/CIDP with SCIg.

Adults and children (0-18 years)

Replacement therapy

The medicinal product should be administered via the subcutaneous route.

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

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. A loading dose of at least 0.2 to0.5 g/kg (1.0 to 2.5 ml/kg) body weight may be required. This may need to be divided over severaldays. After steady state IgG levels have been attained, maintenance doses are administered at repeatedintervals to reach a cumulative monthly dose of the order of 0.4 to 0.8 g/kg (2.0 to 4.0 ml/kg) bodyweight. Each single dose may need to be injected at different anatomic sites.

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 intervalmay 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 recommendedsubcutaneous dose is 0.2 to 0.4 g/kg body weight per week administered in 1 or 2 sessions over 1 or2 consecutive days. The initial subcutaneous dose may be a 1:1 conversion from the previous IVIGdose (calculated as weekly dose).

Example a 1 g/kg IVIG dose given every 3 weeks would convert into a 0.33 g/kg weekly Hizentradose.

The weekly dose can be divided into smaller doses and administered by desired number of times perweek. For dosing every two weeks, double the weekly Hizentra dose.

The dose may need to be adapted to achieve the desired clinical response. Patient`s individual clinicalresponse should be the primary consideration in dose adjustment. In case of clinical deterioration thedose may be increased to the recommended maximum of 0.4 g/kg weekly dose.

Hizentra maintenance therapy in CIDP has not been studied for periods longer than 18 months.

Individualize the duration of any treatment beyond 18 months based upon the patient’s response anddemonstrated need for continued therapy.

Efficacy of Hizentra has been demonstrated over placebo after switching from intravenousimmunoglobulins (IVIG). Direct comparative data for Hizentra versus IVIG are not available. Pleaserefer also to section 5.1.

The posology in children and adolescents (0-18 years) is not different to that of adults as the posologyfor each indication is given by body weight and adjusted to the clinical outcome in replacementtherapy indications.

Hizentra was evaluated in 68 paediatric subjects with PID aged 2 to <12 years and in 57 adolescentsaged 12 to <18 years. No paediatric-specific dose requirements were necessary to achieve the desiredserum IgG levels. Hizentra has not been evaluated in clinical studies in paediatric patients with CIDPwho are under the age of 18.

As the dose is given by body weight and adjusted to the clinical outcome of the above mentionedconditions, the dose in elderly is not considered to be different from that in subjects 18 to 65 years ofage.

In clinical studies Hizentra was evaluated in 13 subjects with PID >65 years of age and no specificdose adjustments were necessary to achieve the desired serum IgG levels.

In clinical studies Hizentra was evaluated in 61 subjects with CIDP >65 years of age and no specificdose adjustments were necessary to achieve the desired clinical outcome.

For subcutaneous use only.

Home-treatment

Subcutaneous infusion for home treatment must be initiated and monitored by a healthcareprofessional experienced in the guidance of patients for home treatment. The healthcare professionalmust select the appropriate way of infusion (device-assisted or manual push infusion), based onpatient`s individual medical situation and preferences. Infusion devices appropriate for subcutaneousadministration of immunoglobulins can be used. The patient or a caregiver must be instructed andtrained in the use of infusion devices, the keeping of treatment diary, recognition of and measures tobe taken in case of severe adverse reactions.

Hizentra may be infused into sites such as abdomen, thigh, upper arm, and/or lateral hip.

More than one infusion device can be used simultaneously. The amount of product infused into aparticular site may vary. In infants and children, infusion site may be changed every 5-15 ml. In adultsdoses may be given up to 50 ml/site. There is no limit to the number of infusion sites. Infusion sitesshould be at least 5 cm apart.

Infusion rate

Hizentra can be infused using:

* an infusion device, or

* by manual push with a syringe.

The recommended initial infusion rate depends on the individual patient’s needs.

Device-assisted infusion

The initial infusion rate should not exceed 20 ml/hour/site.

If well-tolerated (see also section 4.4), the infusion rate can then gradually be increased to35 ml/hour/site for the subsequent two infusions. Thereafter, if the patient tolerates the initial infusionsat the full dose per site and maximum rate, an increase in the infusion rate of successive infusions maybe considered at the discretion of the patient and based on the healthcare professionals’ judgement.

Manual push infusion

The recommended initial infusion rate should not exceed 0.5 ml/min/site (30 ml/hour/site).

If well-tolerated (see also section 4.4), the infusion rate can be increased up to 2.0 ml/min/site(120 ml/hour/site). Thereafter, if the patient tolerates the initial infusions at the full dose per site andmaximum rate, an increase in the infusion rate of successive infusions may be considered at thediscretion of the patient and based on the healthcare professionals’ judgement.

A 24 or larger (i.e. lower gauge number) needle gauge may be required to allow patients to infuse athigher flow rates. Using smaller needles (i.e. higher gauge number) may make it more difficult tomanually push Hizentra. Only one infusion site per syringe can be infused. If administration with anadditional Hizentra syringe is required, a new sterile injection needle should be used and the infusionsite changed.

If a Hizentra pre-filled syringe is used for the administration by manual push, use of 5 ml, 10 ml or20 ml pre-filled syringe presentation is recommended.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 (seesection 4.4).

Patients with hyperprolinaemia type I or II.

Hizentra must not be given intravascularly.

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

Hizentra is for subcutaneous use only. If Hizentra is accidentally administered into a blood vessel,patients could develop shock.

The recommended infusion rate given under section 4.2 should be adhered to. Patients should beclosely monitored and carefully observed for any adverse events throughout the infusion period.

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

Potential complications can often be avoided by ensuring that patients:− are not sensitive to human normal immunoglobulin, by initially injecting the product slowly(see section 4.2);− are carefully monitored for any symptoms throughout the infusion period. In particular, patientsnaïve to human normal immunoglobulin, patients switched from an alternative product or whenthere has been a long interval since the previous infusion should be monitored during the firstinfusion and for the first hour after the first infusion, in order to detect potential adversereactions.

All other patients should be observed for at least 20 minutes after administration.

Suspicion of allergic or anaphylactic type reactions requires immediate discontinuation of theinjection. In case of shock, standard medical treatment should be administered.

True allergic reactions are rare. They can particularly occur in patients with anti-IgA antibodies whoshould be treated with particular caution. Patients with anti-IgA antibodies, in whom treatment withsubcutaneous IgG products remains the only option, should be treated to Hizentra only under closemedical supervision.

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

Thromboembolism

Arterial and venous thromboembolic events including myocardial infarction, stroke, deep venousthrombosis and pulmonary embolism have been associated with the use of immunoglobulins. Cautionshould be exercised in patients with pre-existing risk factors for thrombotic events (such as advancedage, hypertension, diabetes mellitus and a history of vascular disease or thrombotic episodes, patientswith acquired or inherited thrombophilic disorders, patients with prolonged periods of immobilization,severely hypovolemic patients, patients with diseases which increase blood viscosity). Patients shouldbe informed about first symptoms of thromboembolic events including shortness of breath, pain andswelling of a limb, focal neurological deficits and chest pain and should be advised to contact theirphysician immediately upon onset of symptoms. Patients should be sufficiently hydrated before use ofimmunoglobulins.

Aseptic Meningitis Syndrome (AMS)

AMS has been reported with use of IVIg or SCIg. The syndrome usually begins within several hoursto 2 days following immune globulin treatment. AMS is characterised by the following signs andsymptoms: 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 studies, to rule out other causes of meningitis. Discontinuation of immunoglobulintreatment may result in remission of AMS within several days without sequelae.

Information on safety with respect to transmissible agents

Standard measures to prevent infections resulting from the use of medicinal products prepared fromhuman blood or plasma include selection of donors, screening of individual donations and plasmapools for specific markers of infection and the inclusion of effective manufacturing steps for theinactivation/removal of viruses. Despite this, when medicinal products prepared from human blood orplasma 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 HIV, HBV and HCV andfor the non-enveloped viruses 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.

Interference with serological testing

After infusion 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 allo-antibodies (Coombs’ test).

This medicine contains less than 1 mmol sodium (23 mg) per vial/syringe, that is to say essentially‘sodium-free’.

The same warnings and precautions apply to the paediatric population.

The same warnings and precautions apply to the elderly.

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.

The same interactions may occur in the paediatric population.

The same interactions may occur in the elderly.

Data from prospective clinical trials on the use of human normal immunoglobulin in pregnant womenis limited. Therefore, Hizentra should only be given with caution to pregnant women. Clinicalexperience with immunoglobulins suggests that no harmful effects on the course of pregnancy, or onthe foetus or the neonate are to be expected.

Continued treatment of the pregnant woman ensures a passive immunity for the neonate.

Data from prospective clinical trials on the use of human normal immunoglobulin in breast feedingwomen is limited. Therefore, Hizentra should only be given with caution to breast-feeding mothers.

Clinical experience with immunoglobulins suggests however that no harmful effects on the neonateare to be expected. Immunoglobulins are excreted into the milk and may contribute to the transfer ofprotective antibodies to the neonate.

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

Hizentra 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, fever, vomiting, allergic reactions, nausea, arthralgia, lowblood pressure and moderate low back pain may occur occasionally.

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.

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

For safety with respect to transmissible agents, see section 4.4.

Adverse Reactions (ARs) have been collected in Hizentra clinical trials from 7 phase III studies inpatients with primary immunodeficiency (n = 231), 2 phase IV studies in patients with PID (n = 74),1 phase III study (n = 115), and 1 extension study (n = 82) in patients with CIDP (total N = 502patients; 26,646 infusions). The ADRs reported in these clinical studies are summarised andcategorised according to the MedDRA System Organ Class (SOC and Preferred Term level) andfrequency below.

Frequency per patient or per infusion has been evaluated using the following criteria: 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 categorisedas unknown.

Within each frequency grouping, the adverse reactions are presented in the order of decreasingfrequency.

Frequency of Adverse Drug Reactions (ADR) associated with Hizentra obtained from clinicalstudies and post-marketing surveillance, reporting rate per patient or per infusion

System Organ ADRs (MedDRA Preferred Term, PT) ADR frequency ADR frequency

Class category per patient category per(SOC, MedDRA) infusion

Immune system Hypersensitivity Uncommon Raredisorders Anaphylactic reaction Unknown Unknown

Nervous system Headache Very common Uncommondisorders Dizziness, Migraine Common Rare

Tremor (including Psychomotor Uncommon Rarehyperactivity)

Meningitis aseptic Uncommon Very rare

Burning sensation Unknown Unknown

Cardiac disorders Tachycardia Uncommon Very rare

Vascular disorders Hypertension Common Rare

Flushing Uncommon Rare

Embolic and thrombotic events Unknown Unknown

Gastrointestinal Diarrhoea, Abdominal pain Common Uncommondisorders Nausea, Vomiting Common Rare

Skin and Rash Very common Uncommonsubcutaneous Pruritus, Urticaria Common Raretissue disorders

Musculoskeletal Musculoskeletal pain, Arthralgia Common Uncommonand connectivetissue disorders Muscle spasm, Muscular weakness Uncommon Rare

General disorders Infusion site reaction Very common Very commonand administrationsite conditions Fatigue (including Malaise), Pyrexia Common Uncommon

Chest pain, Influenza like illness, Pain Common Rare

Chills (including Hypothermia) Uncommon Rare

Infusion site ulcer Unknown Unknown

Investigations Blood creatinine increased Uncommon Rare

Clinical trials with Hizentra showed a similar overall safety profile in paediatric and adult patientswith PID.

Hizentra was not evaluated in clinical studies in paediatric patients with CIDP who were under the ageof 18.

The same adverse reactions may occur in the elderly. Information available from clinical trials showedno difference in the safety profile of patients ≥65 years of age than of younger patients.

Postmarketing experience with Hizentra in patients ≥65 years of age shows an overall similar safetyprofile in this age group as in younger patients.

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.

Healthcare professionals are asked to report any suspected adverse reactions via the national reportingsystem listed in Appendix V.

Consequences of an overdose are not known.

Pharmacotherapeutic group: immune sera and immunoglobulins: immunoglobulins, normal human,for extravascular administration, ATC code: J06BA01.

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.

In immunodeficiency, adequate doses of Hizentra may restore abnormally low immunoglobulin Gantibody levels to the normal range and thus help against infections.

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

PID

In the European pivotal prospective open label, single arm and multicentre study, a total of 51 subjectswith 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 0.12 g/kg body weight (bw).

Sustained IgG trough levels with mean concentrations of 7.99 - 8.25 g/l were thereby achievedthroughout the treatment period. Subjects received in total 1,831 weekly Hizentra infusions.

In the US prospective open label, single arm and multicentre study, a total of 49 subjects with primaryimmunodeficiency syndromes aged between 5 and 72 years old were treated with Hizentra for up to15 months. The mean dose administered each week was 0.23 g/kg bw. Sustained IgG trough levelswith a mean concentration of 12.53 g/l were thereby achieved throughout the treatment period.

Subjects received in total 2,264 weekly Hizentra infusions.

No serious bacterial infections were reported during the efficacy period in subjects receiving Hizentraduring clinical studies.

To assess the safety and tolerability of higher infusion rates applied via the manual push and pump-assisted administration, 49 PID subjects aged 2 to 75 years were enrolled in an open-label, multicentre,parallel-arm, nonrandomised phase IV HILO (Hizentra Label Optimization) study and treated with

Hizentra for at least 12 weeks (11 paediatric patients aged 2 to <18, 35 adult patients aged 18 to 65,and 3 geriatric patients aged >65 years). In the first patient group receiving Hizentra via the manualpush technique (n = 16), 2 to 7 infusions per week were administered with the flow rates of 30, 60 and120 ml/hour/site (see section 4.2). In the second patient group receiving Hizentra via pump-assistedadministration (n = 18), weekly Hizentra infusions were administered with 25, 50, 75 and100 ml/hour/site flow rate. In a third group, infusion volumes of 25, 40 and 50 ml per site wereadditionally evaluated in pump-assisted administration of weekly Hizentra doses (n = 15). In all threegroups, each infusion parameter was used for 4 weeks, after which subjects successfully completingrequired minimal number of valid infusions could switch to the next higher infusion parameter.

The primary endpoint was the percentage of subjects responding to a higher infusion parameter:

Group Infusion parameter and responder rate (%)1. manual push 30 ml/hour/site 60 ml/hour/site 120 ml/hour/site -flow rates 100.0% 100.0% 87.5% -2. pump-assisted 25 ml/hour/site 50 ml/hour/site 75 ml/hour/site 100 ml/hour/siteflow rates 77.8% 77.8% 66.7% 61.1%3. pump-assisted 25 ml/site 40 ml/site 50 ml/site -volumes 86.7% 73.3% 73.3% -

Responder: in the pump-assisted group a subject who performed ≥3 valid infusions out of 4 for an infusionparameter; in the manual push group a subject who performed ≥60% of valid infusions for an infusionparameter. An infusion was considered valid, if ≥95% of the planned flow rate/volume per ≥1 infusion site wasachieved.

Overall, the number of infusions without severe local reactions versus the total number of infusions(tolerability) was ≥0.98 in all groups for all infusion parameters. No clinically relevant differences inthe serum IgG trough concentrations were observed between the baseline at day 1 and the end of thestudy in all subjects.

CIDP

The safety, efficacy and tolerability of Hizentra in patients with CIDP has been assessed in amulticentre, double-blind, randomised, placebo-controlled, parallel-group phase III PATH[Polyneuropathy and Treatment with Hizentra] study. 172 adults with definite or probable CIDP whowere previously treated with and responded to IVIg were randomised to weekly 0.2 g/kg bw Hizentra,weekly 0.4 g/kg bw Hizentra or placebo groups, and followed for a subsequent 24 weeks. The meanduration of exposure was 118.9 days in the 0.2 g/kg bw and 129 days in the 0.4 g/kg bw Hizentragroup (maximum exposure up to 167 and 166 days in each group, respectively). Subjects generallyused 4 infusion sites in parallel (up to 8 sites in parallel). In total, 57 subjects received 1514 infusionsin the placebo group, 57 subjects received 2007 infusions in the 0.2 g/kg bw Hizentra group, and58 subjects received 2218 infusions in the 0.4 g/kg bw Hizentra group (in total 5739 infusions).

The primary efficacy endpoint was the percentage of subjects who had a CIDP relapse (defined as a≥1 point increase in adjusted Inflammatory Neuropathy Cause and Treatment [INCAT] scorecompared with baseline) or were withdrawn for any other reason in the Hizentra treatment period.

Both Hizentra doses demonstrated superiority over placebo for the primary endpoint. A statisticallysignificant lower percentage of subjects treated with Hizentra, 32.8% for 0.4 g/kg bw and 38.6% for0.2 g/kg bw, had CIDP relapse or was withdrawn for other reasons compared with 63.2% subjectstreated with placebo (p < 0.001 or p = 0.007, respectively). When only considering relapse, the CIDPrelapse rates were 19.0% for 0.4 g/kg bw Hizentra and 33.3% for 0.2 g/kg bw Hizentra compared with56.1% for placebo (p < 0.001 or p = 0.012, respectively). Accordingly, over the treatment period forup to 24 weeks Hizentra prevented relapse in 81% and 67% of subjects in the 0.4 g/kg bw and 0.2 g/kgbw group, respectively, while in the placebo group 44 % of subjects remained relapse-free.

Time to CIDP relapse (Figure 1) was evaluated, and the corresponding probabilities for CIDP relapsebased on Kaplan-Meier estimates were: placebo, 58.8%; 0.2 /kg bw Hizentra, 35.0%; and 0.4 g/kg bw

Hizentra, 22.4 %. The hazard ratios (95% CI) for the lower dose and higher dose compared to placebowas 0.48 (0.27, 0.85) and 0.25 (0.12, 0.49), respectively.

The difference observed between the 0.2 g/kg bw and the 0.4 g/kg bw Hizentra groups did not reachstatistical significance.

Figure 1. Kaplan-Meier Plot Time to CIDP Relapse

In the efficacy scores (INCAT score, mean grip strength, and Medical Research Council sum score),subjects in both Hizentra dose groups remained stable while subjects in the placebo groupdeteriorated. Subjects in the high dose Hizentra group remained stable in the Rasch-built Overall

Disability Scale (R-ODS) centile score. Subjects in both Hizentra dose groups remained stable inelectrophysiology parameters.

A phase III, multicentre, 48-week open-label extension study enrolled 82 CIDP patients from the

PATH study. The extension study investigated the long-term safety and efficacy of Hizentramaintenance therapy in the two weekly doses, 0.2 g/kg and 0.4 g/kg bw. Due to the study design, thesame subject could receive both doses during the study; 72 subjects received doses of 0.4 g/kg and73 subjects received doses of 0.2 g/kg during the efficacy evaluation period. The mean efficacyevaluation period was 125.8 days (range: 1 - 330) in the 0.2 g/kg, and 196.1 days (range: 1 - 330) inthe 0.4 g/kg bw group. Patients who completed the pivotal PATH study without relapse on 0.4 g/kgbw dose and initially received this dose in the extension study had a relapse rate of 5.6%(1/18 patients). For all patients who received 0.4 g/kg bw in the PATH extension study, 9.7%(7/72 patients) had a relapse. Patients who completed the PATH study without relapse on 0.2 g/kg bwdose and initially received this dose in the extension study had a relapse rate of 50% (3/6 patients). Forall patients who received 0.2 g/kg bw in the extension study, 47.9% (35/73 patients) had a relapse.

Down-titrating patients in the extension study who completed the PATH study on either dose from0.4 g/kg to 0.2 g/kg bw dose was possible in 67.9% of subjects (19/28 patients) without occurrence ofrelapse; all of the 9 relapsers recovered within 4 weeks after treatment with 0.4 g/kg bw dose. Gripstrength, MRC sum score, and R-ODS centile score remained stable as compared to baseline forpatients who never had a relapse in the extension study.

The safety and effectiveness of Hizentra have been established in paediatric subjects 2 to 18 years ofage. Hizentra was evaluated in 68 paediatric subjects with PID 2 to <12 years of age and in57 paediatric subjects 12 to <18 years of age. There were no differences in the pharmacokinetics,safety and efficacy profiles as compared with adult subjects. No paediatric-specific dose adjustmentswere necessary to achieve the desired serum IgG levels. No differences were seen in thepharmacodynamic properties between adult and paediatric study patients with PID.

Hizentra has not been evaluated in clinical studies in paediatric patients with CIDP who are under theage of 18.

No overall differences in safety or efficacy were observed between PID subjects >65 years and PIDsubjects 18 to 65 years of age. In the clinical studies Hizentra was evaluated in 13 patients with PID>65 years of age.

No overall differences in safety or efficacy were observed between CIDP subjects >65 years and CIDPsubjects 18 to 65 years of age. In the clinical studies with CIDP patients, 61 subjects >65 years of agewere treated with Hizentra.

Absorption and Distribution

Following subcutaneous administration of Hizentra, peak serum levels are achieved afterapproximately 2 days.

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

PID

In a clinical phase III trial with Hizentra (n = 46), the subjects achieved sustained trough levels(median 8.1 g/l) over a period of 29 weeks when receiving median weekly doses of 0.06 to0.24 g/kgbw.

Simulations by empirical Population Pharmacokinetic models suggested that comparable IgGexposure levels (AUC0-14days, Cmin, 14days) may be obtained if Hizentra is administered subcutaneouslyevery two weeks using double the weekly dose during maintenance therapy.

These simulations further suggested that comparable serum IgG trough levels can be achieved whenthe weekly maintenance dose of Hizentra is administered in proportional amounts more frequentlythan once a week (e.g. 2 times per week, 3 times per week, 5 times per week or daily).

Simulation of 2-3 missed daily doses resulted in a median serum IgG level decrease of ≤4% comparedto consistent daily dosing. By replacing the missed doses when daily dosing was resumed, the medianconcentration profile recovered within 2 to 3 days. However, if missed doses were not replaced whendosing was resumed, it took up to 5-6 weeks for the IgG trough levels to return to steady-state.

No differences were seen in the pharmacokinetic parameters between adult and paediatric PID studypatients.

No overall differences in the pharmacokinetic parameters were observed between PID subjects>65 years and subjects 18 to 65 years of age.

CIDP

In the PATH study, subjects (n = 172) achieved sustained trough levels over a period of 24 weekswhen receiving weekly doses of 0.2 g/kg bw and 0.4 g/kg bw, respectively. The mean (SD) IgG troughconcentration after Hizentra treatment in the 0.4 g/kg bw group was 20.4 (3.24) g/l and 15.4 (3.06) g/lin the 0.2 g/kg bw group. Simulations with population-pharmacokinetic models in the PATH studysuggest that a comparable IgG exposure (Cmax, AUC0-14days, Cmin, 14 days) is achieved when the doubleweekly Hizentra dose is administered every two weeks in the CIDP subjects. These simulations furthersuggest that a comparable IgG exposure is correspondingly achieved when the weekly maintenancedose of Hizentra is divided in several, more frequent doses (2 to 7 times per week) in the CIDPpatients` population.

Hizentra has not been evaluated in clinical studies in paediatric patients with CIDP who are under theage of 18.

No overall differences in the pharmacokinetic parameters were observed between CIDP subjects>65 years and subjects 18 to 65 years of age.

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 theexcipient L-proline. Non-clinical data reveal no special risk for humans based on safety pharmacologyand toxicity studies.

L-proline

Polysorbate 80

Water for injections

Hydrochloric acid (for pH-adjustment)

Sodium hydroxide (for pH adjustment)

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

30 months

Once a vial or the blistered pre-filled syringe has been opened, the solution should be usedimmediately.

Do not store above 25 °C.

Do not freeze.

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

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

Vials5, 10 or 20 ml of solution in a vial (type I glass) and 50 ml of solution in a vial (type II glass), with astopper (halobutyl), a cap (aluminium crimp) and a flip off disc (plastic).

Pack sizes of 1, 10 or 20 vials:1 g/5 ml2 g/10 ml4 g/20 ml10 g/50 ml

Pre-filled syringes5, 10, 20 or 50 ml of solution in a pre-filled syringe (cyclo-olefin-copolymer (COC)) blistered with anoxygen absorber pack.

Pack sizes of 1 pre-filled syringe:1 g/5 ml2 g/10 ml4 g/20 ml10 g/50 ml

Pack sizes of 10 pre-filled syringes:1 g/5 ml2 g/10 ml4 g/20 ml

Alcohol swabs, needles and other supplies or equipment are not contained in the pack.

Not all pack sizes may be marketed.

Hizentra comes as a ready-to-use solution in single-use vials or single-use pre-filled syringes. Hizentrashould be used/infused as soon as possible after opening the vial or blistered pre-filled syringe. Do notuse Hizentra if the vial or blistered pre-filled syringe is open or defective.

The medicinal product should be brought to room or body temperature before use.

The solution should be clear and pale-yellow or light-brown.

Solutions that are cloudy or have deposits should not be used.

Any unused medicinal product, waste material and the oxygen absorber pack should be disposed of inaccordance with local requirements.

CSL Behring GmbH

Emil-von-Behring-Strasse 76

D-35041 Marburg

Germany

Vials

EU/1/11/687/001

EU/1/11/687/002

EU/1/11/687/003

EU/1/11/687/004

EU/1/11/687/005

EU/1/11/687/006

EU/1/11/687/010

EU/1/11/687/011

EU/1/11/687/012

EU/1/11/687/013

EU/1/11/687/014

Pre-filled syringes

EU/1/11/687/015

EU/1/11/687/016

EU/1/11/687/017

EU/1/11/687/018

EU/1/11/687/019

EU/1/11/687/020

EU/1/11/687/023

Date of first authorisation: 14 April 2011

Date of first renewal: 18 February 2016

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

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