HYQVIA 100mg / ml subcutaneous infusion solution medication leaflet

HyQvia 100 mg/mL solution for infusion for subcutaneous use

HyQvia is a dual vial unit consisting of one vial of human normal immunoglobulin(Immune Globulin 10% or IG 10%) and one vial of recombinant human hyaluronidase (rHuPH20).

Human normal immunoglobulin (SCIg)*

One mL contains:

Human normal immunoglobulin. 100 mg(purity of at least 98% IgG)

Each vial of 25 mL contains: 2.5 g of human normal immunoglobulin.

Each vial of 50 mL contains: 5 g of human normal immunoglobulin.

Each vial of 100 mL contains: 10 g of human normal immunoglobulin.

Each vial of 200 mL contains: 20 g of human normal immunoglobulin.

Each vial of 300 mL contains: 30 g of human normal immunoglobulin.

Distribution of the IgG subclasses (approx. values):

IgG1 ≥ 56.9%

IgG2 ≥ 26.6%

IgG3 ≥ 3.4%

IgG4 ≥ 1.7%

The maximum IgA content is 140 micrograms/mL.

*Produced from the plasma of human donors.

Recombinant human hyaluronidase (rHuPH20)

One mL contains:

Recombinant human hyaluronidase. 160 units

Each vial of 1.25 mL contains: 200 units of recombinant human hyaluronidase.

Each vial of 2.5 mL contains: 400 units of recombinant human hyaluronidase.

Each vial of 5 mL contains: 800 units of recombinant human hyaluronidase.

Each vial of 10 mL contains: 1600 units of recombinant human hyaluronidase.

Each vial of 15 mL contains: 2400 units of recombinant human hyaluronidase.

* Recombinant human hyaluronidase (rHuPH20)

The rHuPH20 is a purified glycoprotein of 447 amino acids produced in Chinese Hamster Ovary(CHO) cells by recombinant DNA technology.

* Sodium (as chloride and as phosphate)

The total sodium content of recombinant human hyaluronidase is 4.03 mg/mL.

For the full list of excipients, see section 6.1.

Solution for infusion.

IG 10% is a clear or slightly opalescent and colourless or pale-yellow solution. The solution has apH of 4.6 to 5.1 and an osmolality of 240 to 300 mOsmol/kg.

rHuPH20 is a clear, colourless solution. The solution has a pH of 6.5 to 8.0 and an osmolality of290 to 350 mOsmol/kg.

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

* Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) as maintenance therapyafter stabilisation with IVIg.

Therapy should be initiated and monitored under the supervision of a physician experienced in thetreatment of immune system disorders.

The medicinal product should be administered via the subcutaneous (SC) route. The dose anddose regimens are dependent on the indication.

The dose may need to be individualised for each patient dependent on the pharmacokinetic (PK)and clinical response. Dose based on bodyweight may require adjustment in underweight oroverweight patients. The following dose regimens are given as a guideline.

Replacement therapy in PID

Patients naïve to immunoglobulin therapy

The dose required to achieve a trough IgG level of 6 g/L is of the order of 0.4 to 0.8 g/kg body weightper month. The dose interval to maintain steady-state levels varies from 2-to-4 weeks.

IgG trough levels should be measured and assessed in conjunction with the incidence of infection.

To reduce the rate of infection, it may be necessary to increase the dose and aim for higher

IgG trough levels (> 6 g/L).

At the initiation of therapy, it is recommended that the treatment intervals for the first infusions begradually prolonged from a 1-week dose to up to a 3 -or 4-week dose. The cumulative monthly dose of

IG 10% should be divided into 1-week, 2-week etc. doses according to the planned treatment intervalswith HyQvia.

Patients previously treated with Intravenous immunoglobulin (IVIg)

For patients switching directly from IVIg, or who have a previous IVIg dose that can be referenced,the medicinal product should be administered at the same dose and at the same frequency as theirprevious IVIg treatment. If patients were previously on a 3-week dosing regimen, increasingthe interval to 4-weeks can be accomplished by administering the same weekly equivalents.

Patients previously treated with subcutaneous immunoglobulin (SCIg)

The initial dose of the medicinal product is the same as for SCIg treatment but may be adjusted to3- or 4-weeks interval. The first infusion should be given one week after the last treatment with theprevious immunoglobulin.

Replacement therapy in SID

The recommended dose is 0.2 to 0.4 g/kg every 3 to 4 weeks.

IgG trough levels should be measured and assessed in conjunction with the incidence of infection.

Dose should be adjusted as necessary to achieve optimal protection against infections, an increase maybe necessary in patients with persisting infection; a dose decrease can be considered when the patientremains infection free.

Immunomodulatory therapy in CIDP

Before initiating therapy, the weekly equivalent dose should be calculated by dividing the planneddose by the planned dose interval in weeks. The typical dosing interval range for HyQvia is3 -to 4 - weeks. The recommended subcutaneous dose is 0.3 to 2.4 g/kg body weight per month,administered in 1-or 2-sessions over 1-or 2-days.

The patient’s clinical response should be the primary consideration in dose adjustment. The dose mayneed to be adapted to achieve the desired clinical response. In clinical deterioration, the dose may beincreased to the recommended maximum of 2.4 g/kg monthly. If the patient is clinically stable,periodic dose reductions may be needed to observe whether the patient still needs IG therapy.

A titration schedule that permits gradual dose increase over time (ramp-up) is recommended to ensurethe patient’s tolerability until the full dose is reached. During the titration schedule, the calculated

HyQvia dose and recommended dose intervals must be followed for the first and second infusions.

Depending on the treating physician's discretion, in patients who tolerate the first 2 infusions well,subsequent infusions may be administered by gradually increasing doses and dose intervals,considering the volume and total infusion time. An accelerated titration schedule may be considered ifthe patient tolerates the SC infusion volumes and the first 2 infusions. Doses less than or equal to0.4 g/kg may be administered without a titration schedule, provided acceptable patient tolerance.

Patients must be on stable doses* of IVIg. Before initiating therapy with the medicinal product, theweekly equivalent dose should be calculated by dividing the last IVIg dose by the IVIg dose intervalin weeks. The starting dose and dosing frequency are the same as the patient’s previous IVIgtreatment. The typical dosing interval for HyQvia is 4-weeks. For patients with less frequent IVIgdosing (greater than 4-weeks), the dosing interval can be converted to 4-weeks while maintaining thesame monthly equivalent IgG dose.

As shown in the table below, the calculated one-week dose (1st infusion) should be administered2 - weeks after the last IVIg infusion. One week after the first dose, the next weekly equivalent dose(2nd infusion) should be administered. A titration schedule can take up to 9-weeks (Table 1),depending on the dosing interval and tolerability.

*(Variations in the dosing interval of up to ±7 days or monthly equivalent dose amount of up to ±20%between the subject’s IgG infusions are considered a stable dose.)

Table 1: Recommended IVIg to HyQvia infusion dose titration schedule

Week* Infusion number Dose interval Example for 100 g every 4-weeks1 No infusion2 1st infusion 1-week-dose 25 g3 2nd infusion 1-week-dose 25 g4 3rd infusion 2-week-dose 50 g5 No infusion6 4th infusion 3-week-dose 75 g7 No infusion8 No infusion9 5th infusion 4-week-dose 100 g (Full dose reached)

* 1st infusion starts 2-weeks after the last IVIg dose.

On a given infusion day, the maximum infusion volume should not exceed 1200 mL for patientsweighing ≥ 40 kg or 600 mL for < 40 kg. Suppose the maximum daily dose limit is exceeded or thepatient cannot tolerate the infusion volume. In that case, the dose may be administered over multipledays in divided doses with 48-to 72-hours between doses to allow absorption of infusion fluid at theinfusion site(s). The dose can be administered up to 3 infusion sites with a maximum infusion volumeof 600 mL per site (or as tolerated). If using three sites, the maximum is 400 mL per site.

Replacement therapy

The dosing schedule for children and adolescents (0 to 18 years) is the same as for adults. The dosingis based on body weight and adjusted to the clinical outcome. Currently, available data are describedin sections 4.8, 5.1 and 5.2.

Immunomodulatory therapy

The dosing schedule for children and adolescents (0 to 18 years) is the same as for adults. The dosingis based on the calculated weekly equivalent dose and adjusted to the clinical outcome. Currently,available data are described in sections 4.8, 5.1 and 5.2.

The medicinal product is for subcutaneous use only, do not administer intravenously.

Each vial of IG 10% is supplied with the appropriate corresponding quantity of rHuPH20(see section 6.5). The full contents of the rHuPH20 vial should be administered regardless of whetherthe full content of the IG 10% vial is administered.

The 2 components of the medicinal product must be administered sequentially through the samesubcutaneous needle beginning with the rHuPH20 followed by IG 10%.

Example: Patient is prescribed 110 grams (g) of HyQvia: This will require 3 vials of 30 g and 1 vial of20 g for the total dose of 110 g/1100 mL of the IG 10% component of HyQvia. The volume ofrHuPH20 will be (3 x 15 mL + 1 x10 mL)=55 mL. If the dose is greater than 120 g, HyQvia may beadministered over multiple days in divided doses with 48-to 72-hours between doses to allowabsorption of infusion fluid at the infusion site(s).

Infusion site leakage can occur during or after subcutaneous administration of immunoglobulin,including HyQvia. Consider using longer needles (12 mm or 14 mm) and/or more than one infusionsite. Any change of needle size would have to be supervised by the treating physician.

Home treatment

In case subcutaneous infusion of HyQvia is used for home treatment, therapy should be initiated andmonitored by a physician experienced in the guidance of patients for home treatment. The patient or acaregiver must be instructed in infusion techniques, the use of an infusion pump or syringe driver, thekeeping of a treatment diary, recognition of possible severe adverse reactions and measures to be takenin case these occur.

HyQvia can be administered in a full therapeutic dose at up to 3 infusion sites up to every 4-weeks.

Adjust the frequency and number of infusion sites, considering volume, total infusion time, andtolerability so that the patient receives the same weekly equivalent dose. If a patient misses a dose,administer the missed dose as soon as possible and then resume scheduled treatments as applicable.

Device-assisted infusion

The IG 10% component should be infused using a pump. The rHuPH20 may be hand-pushed orinfused by a pump. A 24-gauge needle may be required to allow patients to infuse at flow rates of300 mL/hr/infusion site. However, needles with smaller diameters may be used if slower flow rates areacceptable. For the 1.25 mL rHuPH20 vial size use an 18-to 22-gauge needle to withdraw the contentsof the vial to prevent stopper push through or coring; for all other vial sizes a needle or needlelessdevice may be used to withdraw the contents of the vial.

Infusion site

The suggested site(s) for the infusion of the medicinal product are the middle to upper abdomen andthighs. If 2 sites are used, the 2 infusion sites should be on contra lateral sides of the body. If usingthree infusion sites, the sites should be at least 10 cm apart. Avoid bony prominences, or scarred areas.

The product should not be infused at or around an infected or acutely inflamed area due to thepotential risk of spreading a localised infection. Avoid at least 5 cm away from the umbilicus.

Infusion rate

It is recommended that the rHuPH20 component be administered at a constant rate and that the rate ofadministration of the IG 10% should not be increased above the recommended rates, particularly whenthe patient has just started with HyQvia therapy.

First, the full dose of rHuPH20 solution is infused at a rate of 1 to 2 mL/minute (or 60 mL/hr to120 mL/hr) per infusion site or as tolerated. Within 10 minutes of the rHuPH20, start the infusion ofthe full dose per site of IG 10% through the same subcutaneous needle set.

The following infusion rates of the IG 10% are recommended per infusion site.

Table 2 : The recommended infusion rates of the IG 10% per infusion site

Subjects < 40 kg Subjects ≥ 40 kg

Subsequent Subsequent

First 2 infusions First 2 infusions

Interval/ 2 to 3 infusions 2 to 3 infusions(mL/hour/infusion (mL/hour/infusion

Minutes (mL/hour/infusion (mL/hour/infusionsite) site)site) site)10 minutes 5 10 10 1010 minutes 10 20 30 3010 minutes 20 40 60 12010 minutes 40 80 120 240

Remainder80 160 240 300of infusion

If the patient tolerates the initial infusions at the full dose per site and maximum rate, an increase inthe rate of successive infusions may be considered at the discretion of the physician and the patient.

For instructions on the handling and preparation of the medicinal product before administration,see section 6.6.

HyQvia must not be given intravenously or intramuscularly.

Hypersensitivity to the active substance (IgG) or to any of the excipients listed insection 6.1 (see section 4.4).

Hypersensitivity to human immunoglobulins, especially in very rare cases of IgA deficiency whenthe patient has antibodies against IgA.

Known systemic hypersensitivity to hyaluronidase or rHuPH20.

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

Precautions for use

If HyQvia is accidentally administered into a blood vessel, patients could develop shock.

The recommended infusion rate given in section 4.2 should be adhered to. Patients must beclosely monitored throughout the infusion period, particularly patients starting with therapy.

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 immunoglobulinproduct is switched or when there has been a long interval since the previous infusion.

Potential complications can often be avoided by:

* initially infusing the product slowly (see section 4.2).

* ensuring that patients are carefully monitored for any symptoms throughout the infusion period.

In particular, patients naive to human normal immunoglobulin, patients switched from analternative immunoglobulin product or when there has been a long interval since the previousinfusion should be monitored during the first infusion and for the first hour after the firstinfusion, to detect potential adverse signs.

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

When treatment is given at home, support from another responsible person should be available fortreating adverse reactions or to summon help should a serious adverse reaction occur. Patients on self-home treatment and/or their guardian should also be trained to detect early signs of hypersensitivityreactions.

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 case of shock,immediately discontinue the infusion and treat the patient for shock.

No chronic changes in the skin were observed in the clinical studies. Patients should be remindedto report any chronic inflammation, nodules or inflammation that occurs at the infusion site andlasts more than a few days.

Hypersensitivity to IG 10%

True hypersensitivity reactions are rare. They can particularly occur in patients with anti-IgAantibodies who should be treated with particular caution. Patients with anti-IgA antibodies, in whomtreatment with SCIg products remains the only option, should be treated with HyQvia 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.

* If a patient is at high risk for any allergic reactions, the medicinal product should beadministered only where supportive care is available for life threatening reactions.

* Patients should be informed of the early signs of anaphylaxis/hypersensitivity (hives, pruritus,generalised urticaria, tightness of the chest, wheezing, and hypotension).

* Depending on the severity of associated reaction, and medical practice, pre-medication mayprevent this type of reaction.

* If known anaphylactic or severe hypersensitivity to human immunoglobulin exists, it shouldbe noted in the patient records.

Hypersensitivity to rHuPH20

Any suspicion of allergic or anaphylactic like reactions following rHuPH20 administration requiresimmediate discontinuation of the infusion and standard medical treatment should be administered, ifnecessary.

Immunogenicity of rHuPH20

Development of non-neutralizing antibodies and neutralizing antibodies to the rHuPH20 componenthas been reported in patients receiving HyQvia in clinical studies. The potential exists for suchantibodies to cross-react with endogenous hyaluronidase, which is known to be expressed in the adultmale testes, epididymis, and sperm. It is unknown whether these antibodies may have any clinicalsignificance in humans (see section 4.8).

Thromboembolism

Arterial and venous thromboembolic events including myocardial infarction, stroke, deep venousthrombosis, and pulmonary embolism have been associated with the use of immunoglobulins. Patientsshould be sufficiently hydrated before using immunoglobulins. Caution should be exercised in patientswith pre-existing risk factors for thromboembolic events (such as advanced age, hypertension, diabetesmellitus and a history of vascular disease or thrombotic episodes, patients with acquired or inheritedthrombophilic disorders, patients with prolonged periods of immobilization, severely hypovolaemicpatients, patients with diseases which increase blood viscosity). Monitor for signs and symptoms ofthrombosis and assess blood viscosity in patients at risk for hyperviscosity. Thrombosis may alsooccur in the absence of known risk factors.

Patients should be informed about first symptoms of thromboembolic events including shortness ofbreath, pain and swelling of a limb, focal neurological deficits and chest pain and should be advised tocontact their physician immediately upon onset of symptoms.

Haemolytic anaemia

Immunoglobulin products contain antibodies to blood groups (e.g. A, B, D) which may act ashaemolysins. These antibodies bind to red blood cells (RBC) epitopes (which may be detected as apositive direct antiglobulin test [DAT, (Coombs’ test)] and, rarely, may cause haemolysis.

Immunoglobulin product recipients should be monitored for clinical signs and symptoms ofhaemolysis.

Aseptic meningitis syndrome (AMS)

Aseptic meningitis syndrome has been reported to occur in association with IVIg and SCIg treatment;the symptoms usually begin within several hours to 2 days following immunoglobulin treatment.

Patients should be informed about the first symptoms which encompass severe headache, neckstiffness, drowsiness, fever, photophobia, nausea, and vomiting. Discontinuation of immunoglobulintreatment may result in remission of AMS within several days without sequelae. Cerebrospinal fluidstudies are frequently positive with pleocytosis up to several thousand cells per mm3, predominantlyfrom 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) IVIg treatment. Frompost-marketing data no clear correlation of AMS to higher doses was observed. Higher incidences of

AMS were seen in women.

Interference with serological testing

After infusion of immunoglobulins, the transitory rise of the various passively transferred antibodiesin the patient’s blood may result in misleading positive results in serological testing.

Passive transmission of antibodies to erythrocyte´s surface antigens, (e.g., A, B, D) may interfere withsome serological tests for red cell antibodies for example the direct antiglobulin test (DAT, direct

Coombs’ test).

Infusions of immunoglobulin products may lead to false positive readings in assays that depend ondetection of β-D-glucans for diagnosis of fungal infections; this may persist during the weeksfollowing infusion of the product.

Transmissible agents

Human normal immunoglobulin and human serum albumin (stabilizer of the rHuPH20) are producedfrom human plasma. Standard measures to prevent infections resulting from the use of medicinalproducts prepared from human blood or plasma include selection of donors, screening of individualdonations and plasma pools for specific markers of infection and the inclusion of effectivemanufacturing steps for the inactivation/removal of viruses. Despite this, when medicinal productsprepared from human blood or plasma are administered, the possibility of transmitting infectiousagents cannot be totally excluded. This also applies to unknown or emerging viruses and otherpathogens.

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

A (HAV) and parvovirus B19 viruses.

There is reassuring clinical evidence regarding the lack of hepatitis A or parvovirus B19 transmissionwith immunoglobulins and it is also assumed that the antibody content makes an importantcontribution to viral safety.

The IG 10% component is essentially sodium-free. The rHuPH20 contains the following amount (mg)of sodium per vial:

1.25 mL contains 5.0 mg of sodium.

2.5 mL contains 10.1 mg of sodium.

5 mL contains 20.2 mg of sodium.

10 mL contains 40.3 mg of sodium.

15 mL contains 60.5 mg of sodium.

This is equivalent to 0.25 to 3% of the WHO recommended maximum daily intake of 2 g sodium foran adult.

The listed warnings and precautions apply both to adults and children.

Live attenuated virus vaccines

Immunoglobulin administration may impair for a period of at least 6-weeks and up to 3-monthsthe efficacy 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 vaccinationwith live attenuated virus vaccines. In the case of measles, this impairment may persist for upto 1 year. Therefore, patients receiving measles vaccine should have their antibody status checked.

The listed interactions apply both to adults and children.

The safety of this medicinal product for use in human pregnancy has not been established in controlledclinical studies and therefore should only be given with caution to pregnant women and breast-feedingmothers.

Nine women ever treated with HyQvia were enrolled in a prospective, uncontrolled, multicentrepost- authorisation Pregnancy Registry (Study 161301). Of the 8 pregnancies with known outcomes,there were 8 live births with normal APGAR scores. There were no specified labour or deliverycomplications. No adverse events were reported as related to this medicinal product. Four (4) motherswere tested for anti-rHuPH20 binding, or neutralizing antibodies and no antibodies were detected.

Immunoglobulin products have been shown to cross the placenta, increasingly during the thirdtrimester. Clinical experience with immunoglobulins suggests that no harmful effects on the course ofpregnancy, or on the foetus and the neonate are to be expected.

Development and reproductive toxicology studies have been conducted with rHuPH20 in mice andrabbits. No adverse reactions on pregnancy and foetal development were associated withanti-rHuPH20 antibodies. In these studies, maternal antibodies to rHuPH20 were transferred tooffspring in utero. The effects of antibodies to the rHuPH20 component of this medicinal product onthe human embryo or on human foetal development are currently unknown (see section 5.3).

Immunoglobulins are excreted into the milk and may contribute to protecting the neonate frompathogens which have a mucosal portal of entry. One infant in the Pregnancy Registry (Study 161301)was breastfed. All adverse events were reported as not related to previous or current HyQviatreatment.

There are currently no clinical safety data for this medicinal product on fertility available.

Clinical experience with immunoglobulins suggests that no harmful effects of IG 10% on fertilityare to be expected.

Animal studies do not indicate direct or indirect harmful effects of rHuPH20 with respect toreproductive potential at the doses used for facilitating administration of IG 10% (see section 5.3).

The ability to drive and operate machines may be impaired by some adverse reactions e.g., dizziness(see section 4.8) associated with this medicinal product. Patients who experience adverse reactionsduring treatment should wait for these to resolve before driving or operating machines.

IG 10%

Adverse reactions such as chills, headache, dizziness, fever, vomiting, allergic reactions, nausea,arthralgia, low blood 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, may frequently occur.

Cases of transient aseptic meningitis, transient haemolytic reactions, increase in serum creatinine leveland/or acute renal failure have been observed with human normal immunoglobulin, see section 4.4.

Thromboembolic reactions such as myocardial infarction, stroke, pulmonary embolism, and deep veinthrombosis have been rarely observed with IVIg and SCIg products.

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

rHuPH20

The most frequent adverse reactions reported during post-marketing use of rHuPH20 in similarformulations administered subcutaneously for the dispersion and absorption of subcutaneouslyadministered fluids or medicinal products have been mild local infusion site reactions such aserythema and pain. Oedema has been reported most frequently in association with large volumesubcutaneous fluid administration.

Antibodies against rHuPH20

A total of 13 out of 83 subjects who participated in pivotal PID study developed an antibody capableof binding to rHuPH20 at least once during the clinical study. These antibodies were not capable ofneutralizing rHuPH20. No temporal association between adverse reactions and the presence of anti-rHuPH20 antibodies could be demonstrated. There was no increase in incidence or severity of adversereactions in patients who developed antibodies to rHuPH20.

A total of 16 out of 132 patients who received rHuPH20 developed anti-rHuPH20 binding antibodiesat least once in CIDP studies that included 289 patient-years of follow-up. Two subjects developedanti- rHuPH20 neutralizing antibodies. No efficacy or safety issues were identified with binding orneutralizing antibody positivity.

The safety of HyQvia was evaluated in 228 patients who received a total of 7 287 infusions across 6clinical studies. It included 4 clinical studies (160602, 160603, 160902, and 161101) in 124 patientswith PID, who received 3 202 infusions, and 2 clinical studies (161403 Epoch 1 and 161505) in 104patients with CIDP, who received 4 085 HyQvia infusions.

The table presented below is according to the MedDRA (27.1) System Organ Classification (SOC and

Preferred Term Level).

Frequencies have been evaluated using the following convention: 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), not known (cannot be estimated from available data). Within each frequency grouping,undesirable effects are presented in order of decreasing seriousness.

Table 3: Frequency of Adverse drug reactions (ADR) per infusion reported in patients treatedwith HyQvia in clinical studies (160602, 160603, 160902,161101, 161403 Epoch 1 and 161505)and post-marketing surveillance, reporting rate per patient or per infusion.

MedDRA Frequency Frequency

System Organ Adverse drug reactions per patient per infusion

Class (SOC) N=228 N=7,287

Infections and Meningitis aseptic* Not Known Not Known

Infestations

Immune System Hypersensitivity* Not Known Not Knowndisorders

Nervous system Headache Very Common Commondisorders Dizziness Common Uncommon

MedDRA Frequency Frequency

System Organ Adverse drug reactions per patient per infusion

Class (SOC) N=228 N=7,287

Migraine Common Uncommon

Paraesthesia Common Uncommon

Burning sensation Common Uncommon

Tremor Common Rare

Cerebrovascular accident

Uncommon Rareand Ischaemic stroke

Cardiac Sinus tachycardia and

Common Uncommondisorders Tachycardia

Hypertension and Blood

Vascular Very Common Uncommonpressure increaseddisorders

Hypotension Common Rare

Respiratory,thoracic, and

Dyspnoea Common Raremediastinaldisorders

Nausea Very Common Common

Abdominal pain, Abdominalpain lower, Abdominal pain

Very Common Uncommon

Gastrointestinal upper and Abdominaldisorders tenderness

Diarrhoea Very Common Uncommon

Vomiting Very Common Uncommon

Abdominal distension Common Uncommon

Erythema Common Uncommon

Pruritus Common Uncommon

Skin and Rash, Rash erythematous,subcutaneous Rash macular, Rash maculo- Common Uncommontissue disorders papular and Rash papular

Urticaria Common Uncommon

Hyperhidrosis Common Rare

Myalgia Common Uncommon

Arthralgia Very Common Uncommon

Limb discomfort and Pain in

Musculoskeletal Common Uncommonextremityand connective

Back pain Common Uncommontissue disorders

Joint stiffness Uncommon Uncommon

Musculoskeletal chest pain Common Uncommon

Groin pain Common Rare

Renal andurinary Haemosiderinuria Common Raredisorders

MedDRA Frequency Frequency

System Organ Adverse drug reactions per patient per infusion

Class (SOC) N=228 N=7,287

Local reactions (Total) Very Common Very Common

- Infusion site discomfort,

Infusion site pain,

Injection site pain, Very Common Common

Puncture site pain and

Tenderness

- Infusion site erythemaand Injection site Very Common Commonerythema

- Infusion site oedema,

Injection site oedema,

Infusion site swelling, Very Common Common

Injection site swellingand Swelling (local)

- Infusion site pruritus,

Injection site pruritus,

Puncture site pruritus Very Common Commonand Vulvovaginalpruritus

- Infusion related reaction Common Uncommon

- Infusion site bruising,

Injection site bruising,

Infusion site haematoma,

Injection site Common Uncommonhaematoma, Infusion site

Generalhaemorrhage and Vesseldisorders andpuncture site bruiseadministrationsite conditions - Infusion site reaction,

Injection site reaction

Common Uncommonand Puncture sitereaction

- Infusion site mass,

Injection site mass and Common Uncommon

Infusion site nodule

- Infusion site

Common Uncommondiscoloration

- Infusion site rash and

Common Uncommon

Injection site rash

- Infusion site indurationand Injection site Common Uncommoninduration

- Infusion site warmth Common Rare

- Infusion site paraesthesiaand Injection site Common Rareparaesthesia

- Infusion site

Common Rareinflammation

- Infusion site leakage* Not Known Not Known

Feeling hot and Pyrexia Very Common Common

Influenza like illness* Not Known Not Known

MedDRA Frequency Frequency

System Organ Adverse drug reactions per patient per infusion

Class (SOC) N=228 N=7,287

Asthenia, Fatigue, Lethargy

Very Common Commonand Malaise

Chills Common Uncommon

Oedema, Oedema peripheral

Common Uncommonand Swelling (systemic)

Localised oedema,

Peripheral swelling and Skin Common Uncommonoedema

Gravitational oedema,

Oedema genital, Scrotal

Common Uncommonswelling and Vulvovaginalswelling

Coombs direct test positive

Investigations Common Rareand Coombs test positive

* Adverse events from post-marketing surveillance.

The most common local reactions observed during the pivotal clinical studies include infusion sitepain, infusion site erythema and infusion site oedema. Most of the local reactions were mild in severityand self-limited. In the PID studies, 2 instances of local adverse reactions were severe (infusion sitepain and infusion site swelling) and in the CIDP studies 4 instances were severe (infusion siteextravasation, infusion site inflammation, infusion site pruritus and infusion site reaction). In the PIDstudies, there were 2 instances of transient genital oedema, one considered severe, that resulted fromdiffusion of the medicinal product from the infusion site in the abdomen. In the CIDP studies therewas one mild instance of genital oedema (penile swelling). No skin changes were observed that didnot resolve during the clinical study.

PID

In the pivotal study 160603 there were 2 of the 24 paediatric patients with total anti-rHuPH20antibody levels at or above 1:160. None had neutralising antibodies.

A prospective, Phase 4, multicentre study in Europe evaluated 42 paediatric subjects (age2 to < 18 years) who had received prior immunoglobulin therapy (Study 161504). No new safetyconcerns were identified. No subject was positive (titre ≥ 160) for binding antirHuPH20 antibodies.

HyQvia was found to be safe and tolerable among paediatric subjects (2 to < 18 years old) with PIDD.

Results of clinical studies indicate similar safety profiles in adults and paediatric population, includingthe nature, frequency, seriousness, and reversibility of adverse reactions.

CIDP

HyQvia has not been evaluated in clinical studies in children or adolescent patients (0 to 18 years)with CIDP.

Elderly Patients

Primary Immunodeficiency

Post-authorisation safety studies (EU 161302, US 161406) included 15 and 77 elderly subjects,respectively. Overall, no significant safety differences were observed between PID subjects above65 years and those between 18 and 65 years old.

Reporting suspected adverse reactions after authorisation of the medicinal product is important.

It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

The consequences of an overdose are not known.

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

The IG 10% component provides the therapeutic effect of this medicinal product. The rHuPH20facilitates the dispersion and absorption of IG 10%.

Human normal immunoglobulin contains mainly immunoglobulin G (IgG) with a broad spectrum ofopsonising and neutralizing antibodies against infectious agents. Human normal immunoglobulincontains the IgG antibodies present in the normal population. It is usually prepared from pooledhuman plasma from not fewer than 1 000 donations. It has a distribution of IgG subclasses closelyproportional to that in native human plasma. Adequate doses of human normal immunoglobulin mayrestore abnormally low IgG levels to the normal range. The mechanism of action in indications otherthan replacement therapy is not fully elucidated but includes immunomodulatory effects.

Recombinant human hyaluronidase is a soluble recombinant form of human hyaluronidase thatincreases the permeability of the subcutaneous tissue by temporarily depolymerising hyaluronan.

Hyaluronan is a polysaccharide found in the intercellular matrix of the connective tissue. It isdepolymerised by the naturally occurring enzyme hyaluronidase. Unlike the stable structuralcomponents of the interstitial matrix, hyaluronan has a very fast turnover with half-life ofapproximately 0.5 days. The rHuPH20 of HyQvia acts locally. The effects of the hyaluronidase arereversible, and permeability of the subcutaneous tissue is restored within 24 to 48 hours.

PID

Efficacy and safety of HyQvia was assessed in a phase 3 study (160603) in 83 patients with PID.

Patients were treated with it at either 3- or 4-week treatment intervals for a total of 12-months(following a brief titration period). The dose was based on the previous treatment with intravenous

IG 10% (320 to 1 000 mg/kg body weight /4-weeks) and was individually adapted, ensuring adequate

IgG levels throughout the study.

The results of the study showed a rate of validated, acute, serious bacterial infections per year during

HyQvia treatment of 0.025 (upper limit of the one-sided 99% confidence interval 0.046). The overallrate of infections was less during HyQvia administration than during the 3-months intravenousadministration of IG 10%: the point estimate of the annualized rate of all infections was2.97 (95% CI: 2.51 to 3.47) for HyQvia and 4.51 (95% CI: 3.50 to 5.69) for intravenous IG 10%infusions.

Nearly all of the subjects were able to attain the same dose interval with HyQvia as they had forintravenous administration. Seventy-eight (78) of 83 (94%) subjects attained the same 3- or 4-weekdosing whereas one decreased from 4-to 3-weeks, one from 4-to 2-weeks and one from 3-to 2-weeks(2-subjects withdrew during the titration period).

The median number of infusion sites per month for HyQvia was 1.09, which is slightly lower thanthe median number of intravenous IG 10% infusion sites used in this study (1.34), and considerablylower than the median number of infusion sites in the study of subcutaneous administration of

IG 10% (21.43).

Sixty-six (66) patients who completed the pivotal phase 3 study participated in an extension study(160902) for the evaluation of long-term safety, tolerability, and efficacy of HyQvia in PID.

The overall combined exposure of PID patients in both studies was 187.69 patient years; the longestexposure for adults was 3.8-years and 3.3-years for paediatric patients.

Study 161302 (EU):

This non-interventional post-authorisation safety study on the long-term safety of HyQvia in subjectstreated with HyQvia was carried out for approximately 6 years. A total of 111 adult subjects wereenrolled in the study. The mean age of the study population was 46.2 (standard deviation [SD]=14.69)years, and 14.2% (n=15) of the subjects were 65 years or older. Over half of the subjects were female(n=60, 56.6%), of whom 56.7% were of childbearing potential This study confirms the known safetyprofile of HyQvia.

Study 161406 (US):

This non-interventional post-authorisation safety study on the long-term safety of HyQvia was carriedout for approximately 6 years. A total of 253 adult subjects with PID were enrolled. The median agewas 57.0 years, 30.4% (n=77) were 65 years or older, and 79.1% (n=200) were female, 22.5% (n=45)of whom were of childbearing potential. This study confirms the known safety profile of HyQvia.

CIDP

Study 161403 (ADVANCE-1):

In a multicentre, randomized, placebo-controlled, phase 3 study, 132 adult subjects with CIDPunderwent evaluation of the efficacy, safety, and tolerability of HyQvia as a maintenance therapy toprevent relapse that allows self-infusion of a total therapeutic dose every 2- to 4-weeks.

The study enrolled subjects ≥ 18 years of age (male or female) at the time of screening who had adocumented diagnosis of definite or probable CIDP as per the European Federation of Neurological

Societies/Peripheral Nerve Society (EFNS/PNS) 2010 criteria. All eligible subjects had responded to

IgG treatment in the past (partial or complete resolution of neurological symptoms and deficits) andwere on a stable dose of IVIg treatment within the dose range equivalent to a cumulative monthly doseof 0.4 to 2.4 g/kg body weight administered intravenously for at least 12-weeks before screening.

The primary endpoint was the proportion of subjects who experienced a relapse, defined as anincrease of ≥ 1 point relative to the pre-SC treatment baseline score in 2 consecutive adjustedinflammatory neuropathy cause and treatment (INCAT) disability scores obtained less than seven daysapart. The analysis of the primary endpoint employing appropriate post-hoc strategies to handleintercurrent events and missing outcome values using multiple imputation revealed a relapse rate of15.5% (95% CI: 8.36, 26.84) in the HyQvia and 31.7% (95% CI: 21.96, 43.39) in the placebo groups.

The treatment difference was -16.2 (95% CI: -29.92, -1.27), favouring HyQvia over placebo.

Study 161505 (ADVANCE-3):

Study 161505 was a Phase 3b, long-term, multicentre study of HyQvia subcutaneous treatment inadult subjects with CIDP who had received prior HyQvia therapy (or placebo) in Study 161403. Theprimary objective of the study was to collect long-term data on the safety, tolerability, and efficacy (asexploratory measures only) of HyQvia in the subject population. Enrollment into this study was opento subjects who completed Study 161403 Epoch 1 without CIDP worsening. A total of 85 subjectswho completed Study 161403 and met the selection criteria for Study 161505 were enrolled andtreated. The mean duration of exposure to HyQvia was 31.1 months (range: 0 to 77.3). The totalexposure time was 219.9 patient-years. The safety outcomes confirmed the known safety profile of

HyQvia and did not reveal any new safety concerns. A total of 10 subjects of the 77 evaluable subjectsdeveloped a CIDP relapse during the study. The 6-month and annual relapse rates were 0.023 and0.045, respectively.

PID

In the pivotal studies, HyQvia was evaluated in 24 paediatric patients, including 13 patientsbetween 4 and < 12 years and 11 between 12 and < 18 years, who were treated for up to 3.3-years withan overall safety experience equivalent to 48.66 patient years (as described in section Clinical efficacyand safety). No appreciable differences in the pharmacodynamic effects or efficacy and safety of

HyQvia were observed between paediatric patients and adults. See sections 4.2 and 4.8.

The medicinal product was evaluated in 42 paediatric subjects (age 2 to < 18 years), in a Phase 4,non-controlled, multicentre study in paediatric subjects who had received prior immunoglobulintherapy. No new safety concerns were identified in paediatric subjects with PID.

The European Medicines Agency has deferred the obligation to submit the results of studies with

HyQvia in one or more subsets of the paediatric population in treatment of PID as model forreplacement therapy. See section 4.2 for information on paediatric use.

CIDP

HyQvia has not been evaluated in clinical studies in children or adolescent patients (0 to 18 years)with CIDP.

Following subcutaneous administration of HyQvia in PID patients, peak serum IgG levels areachieved in the recipient’s circulation after approximately 3 to 5 days.

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

PID

The pharmacokinetics (PK) of HyQvia were evaluated in a clinical study (160601, 160602 and160603) in patients with PID aged 12 years and older. Data from the PID clinical studies show thatserum IgG trough levels can be maintained by dosing regimens of 320 to 1 000 mg/kg bodyweight/4-weeks given at intervals of 3- or 4-weeks.

The pharmacokinetic results are presented in the table below, as compared to data for intravenousadministration of IG 10% obtained in the same study.

Table 4: Pharmacokinetic Parameters of HyQvia Compared to Intravenous Administration of

IG 10%

HyQvia IVIG 10%

Parameter Median (95% Cl) Median (95% Cl)

N=60 N=68

Cmax [g/l] 15.5 (14.5; 17.) 21.9 (20.7; 23.9)

Cmin [g/l] 10.4 (9.4 to 11.2) 10.1 (9.5 to 10.9)

AUC per week [g*days/l] 90.52 (83.8 to 9) 93.9 (89.1 to 102.1)

Tmax [days] 5.0 (3.3 to 5.1) 0.1 (0.1 to 0.1)

Apparent clearance or clearance [mL/kg/day] 1.6 (1.4 to 1.79) 1.4 (1.2 to 1.4)

Terminal half-life [days] 45.3 (41.0 to 60.2) 35.7 (32.4 to 40.4)

CIDP

The complete pharmacokinetic profile of HyQvia was not evaluated in the clinical study (161403) inpatients with CIDP aged 18 years and older. Only the serum trough levels of total IgG were assessedthroughout the study. Overall, during the treatment periods with HyQvia, serum trough levels of total

IgG remained stable. For subjects who developed a relapse and switched to IVIg (n=6), the serumtrough levels of total IgG also appeared stable throughout the treatment periods on HyQvia or IVIg.

The median serum trough levels of total IgG in CIDP were approximately 40% greater than in PID.

PID

In the clinical study with HyQvia, no differences in the plasma IgG trough levels were observedbetween adult and paediatric patients.

CIDP

HyQvia has not been evaluated in clinical studies in children or adolescent patients (0 to 18 years)with CIDP.

Immunoglobulins are normal constituents of the human body.

The safety of IG 10% has been demonstrated in several non-clinical studies. Non-clinical data revealno special risk for humans based on conventional studies of safety pharmacology and toxicity. Studiesof repeated dose toxicity, genotoxicity, and toxicity to reproduction in animals are impracticable dueto induction of and interference by developing antibodies to heterologous proteins.

Long term animal studies to evaluate the carcinogenic or mutagenic potential of rHuPH20 have notbeen conducted. No adverse reactions on fertility were observed in mice, rabbits and cynomolgusmonkeys exposed to antibodies that bind to rHuPH20 and species-specific hyaluronidase. Reversibleinfertility has been observed in male and female guinea pigs immunized to produce antibodies tohyaluronidase. However, antibodies to hyaluronidase did not influence reproduction followingimmunization of mice, rabbits, sheep, or cynomolgus monkeys. The effects of antibodies that bind torHuPH20 on human fertility are unknown.

Human normal immunoglobulin (IG 10%) vial

Glycine

Water for injections

Recombinant human hyaluronidase (rHuPH20) vial

Sodium chloride

Sodium phosphate dibasic

Human albumin

Ethylenediaminetetraacetic acid (EDTA) disodium

Calcium chloride

Sodium hydroxide (for pH adjustment)

Hydrochloric acid (for pH adjustment)

Water for injections

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

3-years.

Store in a refrigerator (2 °C - 8 °C).

The product may be stored at temperatures above +8°C and below +25°C for up to 3 months. Do notrefrigerate after storing at room temperature. Discard after 3 months or after the expiry date is reachedwhichever occurs sooner.

The date of removal from the refrigerator should be recorded on the outer carton.

Do not freeze.

Keep the vials in the outer carton in order to protect them from light.

Human normal immunoglobulin (IG 10%) vial25, 50, 100, 200 or 300 mL of solution in a vial (Type I glass) with a stopper (bromobutyl rubber).

Recombinant human hyaluronidase (rHuPH20) vial1.25, 2.5, 5, 10 or 15 mL of solution in a vial (Type I glass) with a stopper (chlorobutyl rubber).

One vial of IG 10% and one vial of rHuPH20 in a dual vial unit.

Not all pack sizes may be marketed.

The medicinal product should be brought to room temperature before use. Do not use heating devicesincluding microwaves.

IG 10% is a clear or slightly opalescent and colourless or pale-yellow solution. rHuPH20is a clear,colourless solution.

This medicinal product is comprised of 2 vials. Both vials should be inspected visually for particulatematter and discoloration prior to administration. Solutions that are cloudy or have deposits should notbe used.

Do not shake.

Do not mix the components of HyQvia prior to administration.

Do not use vented vial access devices to remove rHuPH20from vials.

Use aseptic technique when preparing and administering HyQvia. In cases where more than onevial of the medicinal product IG 10% or rHuPH20 is required to obtain the required dose of theinfusion, the IG 10% and/or rHuPH20should be prepared separately in appropriate solution containersbefore administration. Partially used vials should be discarded.

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

Baxalta Innovations GmbH

Industriestrasse 67

A-1221 Vienna, Austria

EU/1/13/840/001

EU/1/13/840/002

EU/1/13/840/003

EU/1/13/840/004

EU/1/13/840/005

Date of first authorisation: 16 May 2013

Date of renewal: 8 Jan 2018

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

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