KIOVIG 100mg / ml infusion solution medication leaflet

KIOVIG 100 mg/ml solution for infusion

Human normal immunoglobulin (IVIg)

One ml contains:

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

Each vial of 10 ml contains: 1 g of human normal immunoglobulin

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 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.

For the full list of excipients, see section 6.1.

Solution for infusion

The solution is clear or slightly opalescent and colourless or pale yellow.

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

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

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

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

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

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

- Guillain Barré syndrome.

- Kawasaki disease (in conjunction with acetylsalicylic acid; see 4.2).

- Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).

- Multifocal Motor Neuropathy (MMN).

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

The dose and dose regimen is dependent on the indication.

In replacement therapy the dose may need to be individualised for each patient dependent on thepharmacokinetic and clinical response. Dose based on bodyweight may require adjustment inunderweight or overweight patients.

The following dose regimens are given as a guideline.

Replacement therapy in primary immunodeficiency syndromes

The dose regimen should achieve a trough level of IgG (measured before the next infusion) of atleast 5 to 6 g/L. Three to six months are required after the initiation of therapy for equilibration(steady-state IgG levels) to occur. The recommended starting dose is 0.4-0.8 g/kg given once,followed by at least 0.2 g/kg given every three to four weeks.

The dose required to achieve a trough level of 5-6 g/L is of the order of 0.2-0.8 g/kg/month.

The dose interval when steady state has been reached varies from 3-4 weeks.

IgG trough levels should be measured and assessed in conjunction with the incidence of infection. Toreduce the rate of bacterial infection, it may be necessary to increase the dose and aim for highertrough levels.

Secondary immunodeficiencies (as defined in 4.1.)

The recommended dose is 0.2-0.4 g/kg every three to four weeks.

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

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

Primary immune thrombocytopenia

There are two alternative treatment schedules:

- 0.8-1g/kg given on day one; this dose may be repeated once within 3 days

- 0.4 g/kg given daily for two to five days.

The treatment can be repeated if relapse occurs.

Guillain Barré syndrome0.4 g/kg/day over 5 days (possible repeat of dosing in case of relapse).

Kawasaki Disease2 g/kg should be administered as a single dose. Patients should receive concomitant treatment withacetylsalicylic acid.

Chronic inflammatory demyelinating polyneuropathy (CIDP)

Starting dose: 2 g/kg divided over 2 -5 consecutive days

Maintenance doses:1 g/kg over 1-2 consecutive days every 3 weeks.

The treatment effect should be evaluated after each cycle; if no treatment effect is seen after 6 months,the treatment should be discontinued.

If the treatment is effective long term treatment should be subject to the physicians discretion basedupon the patient response and maintenance response. The dosing and intervals may have to be adaptedaccording to the individual course of the disease.

Multifocal Motor Neuropathy (MMN)

Starting dose: 2 g/kg given over 2-5 consecutive days.

Maintenance dose: 1 g/kg every 2 to 4 weeks or 2 g/kg every 4 to 8 weeks over 2-5 days.

The treatment effect should be evaluated after each cycle; if no treatment effect is seen after 6 months,the treatment should be discontinued.

If the treatment is effective long term treatment should be subject to the physicians discretion basedupon the patient response and maintenance response. The dosing and intervals may have to be adaptedaccording to the individual course of the disease.

The dose recommendations are summarised in the following table:

Indication Dose Frequency of injections

Replacement therapy in primary starting dose:immunodeficiency 0.4-0.8 g/kgmaintenance dose: every 3-4 weeks to obtain IgG0.2-0.8 g/kg trough level of at least 5-6 g/l

Replacement therapy in secondary 0.2-0.4 g/kg every 3-4 weeks to obtain IgGimmunodeficiency trough level of at least 5-6 g/l

Immunomodulation:

Primary immune thrombocytopenia 0.8-1 g/kg on day 1, possibly repeated oncewithin 3 daysor0.4 g/kg/d for 2-5 days

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

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

Chronic inflammatory demyelinating starting dose In divided doses over 2-5 dayspolyradiculoneuropathy (CIDP) 2g/kgmaintenance dose: every 3 weeks over 1-2 days1g/kg

Multifocal Motor Neuropathy (MMN) starting given over 2-5 daysdose: 2 g/kgmaintenance every 2-4 weeksdose: 1 g/kgor or2 g/kg every 4-8 weeks over 2-5 days

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

No evidence is available to require a dose adjustment.

No dose adjustment unless clinically warranted, see section 4.4.

No dose adjustment unless clinically warranted, see section 4.4.

For intravenous use.

Human normal immunoglobulin should be infused intravenously at an initial rate of 0.5 ml/kg BW/hrfor 30 minutes. If well tolerated (see section 4.4), the rate of administration may gradually beincreased to a maximum of 6 ml/kg BW/hr. Clinical data obtained from a limited number of patientsalso indicate that adult PID patients may tolerate an infusion rate of up to 8 ml/kg BW/hr. For furtherprecautions for use see section 4.4.

If dilution prior to infusion is required, KIOVIG may be diluted with 5% glucose solution to a finalconcentration of 50 mg/ml (5% immunoglobulin). For instructions on dilution of the medicinalproduct before administration, see section 6.6.

Any infusion-related adverse events should be treated by lowering infusion rates or by stopping theinfusion.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Hypersensitivity to human immunoglobulins, especially in patients with antibodies against IgA.

Patients with selective IgA deficiency who developed antibodies to IgA, as administering an IgAcontaining product can result in anaphylaxis.

Infusion reaction

Certain severe adverse reactions (e.g. headache, flushing, chills, myalgia, wheezing, tachycardia,lower back pain, nausea, and hypotension) may be related to the rate of infusion. The recommendedinfusion rate given under section 4.2 must be closely followed. Patients must be closely monitored andcarefully observed for any symptoms throughout the infusion period.

Certain adverse reactions may occur more frequently

- in case of high rate of infusion

- in patients who receive human normal immunoglobulin for the first time or, in rare cases, whenthe human normal immunoglobulin product is switched or when there has been a long intervalsince the previous infusion.

- in patients with an untreated infection or underlying chronic inflammation.

Precautions for use

Potential complications can often be avoided by ensuring that patients:

- are not sensitive to human normal immunoglobulin by initially injecting the product slowly(0.5 ml/kg BW/hr);

- are carefully monitored for any symptoms throughout the infusion period. In particular, patientsnaive to human normal immunoglobulin, patients switched from an alternative IVIg product orwhen there has been a long interval since the previous infusion should be monitored at thehospital during the first infusion and for the first hour after the first infusion, in order to detectpotential adverse signs. All other patients should be observed for at least 20 minutes afteradministration.

In all patients, IVIg administration requires:

- adequate hydration prior to the initiation of the infusion of IVIg

- monitoring of urine output

- monitoring of serum creatinine levels

- monitoring for signs and symptoms of thrombosis

- assessment of blood viscosity in patients at risk for hyperviscosity

- avoidance of concomitant use of loop diuretics (see 4.5).

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.

If dilution of KIOVIG to lower concentrations is required for patients suffering from diabetes mellitus,the use of 5% glucose solution for dilution may have to be reconsidered.

Hypersensitivity reactions are rare.

Anaphylaxis can develop in patients

- with undetectable IgA who have anti-IgA antibodies

- who had tolerated previous treatment with human normal immunoglobulin

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

Thromboembolism

There is clinical evidence of an association between IVIg administration and thromboembolic eventssuch as myocardial infarction, cerebral vascular accident (including stroke), pulmonary embolism anddeep vein thromboses which is assumed to be related to a relative increase in blood viscosity throughthe high influx of immunoglobulin in at-risk patients. Caution should be exercised in prescribing andinfusion of IVIg in obese patients and in patients with pre-existing risk factors for thrombotic events(such as a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impairedcardiac output, hypertension, use of estrogens, diabetes mellitus and a history of vascular disease orthrombotic episodes, patients with acquired or inherited thrombophilic disorders, hypercoagulabledisorders, patients with prolonged periods of immobilisation, severely hypovolaemic patients, patientswith diseases which increase blood viscosity, patients with indwelling vascular catheters and patientswith high dose and rapid infusion).

Hyperproteinemia, increased serum viscosity and subsequent relative pseudohyponatremia may occurin patients receiving IVIg therapy. This should be taken into account by physicians, since initiation oftreatment for true hyponatremia (i.e. decreasing serum free water) in these patients may lead toa further increase in serum viscosity and a possible predisposition to thromboembolic events.

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

Cases of acute renal failure have been reported in patients receiving IVIg therapy. These include acuterenal failure, acute tubular necrosis, proximal tubular nephropathy and osmotic nephrosis. In mostcases, risk factors have been identified, such as pre-existing renal insufficiency, diabetes mellitus,hypovolaemia, overweight, concomitant nephrotoxic medicinal products, age over 65, sepsis,hyperviscosity or paraproteinemia.

Renal parameters should be assessed prior to infusion of IVIg, particularly in patients judged to have apotential increased risk for developing acute renal failure, and again at appropriate intervals. Inpatients at risk for acute renal failure, IVIg products should be administered at the minimum rate ofinfusion and dose practicable. In case of renal impairment, IVIg discontinuation should be considered.

While these reports of renal dysfunction and acute renal failure have been associated with the use ofmany of the licensed IVIg products containing various excipients such as sucrose, glucose andmaltose, those containing sucrose as a stabiliser accounted for a disproportionate share of the totalnumber. In patients at risk, the use of IVIg products that do not contain these excipients may beconsidered. KIOVIG does not contain sucrose, maltose or glucose.

Transfusion Related Acute Lung Injury (TRALI)

In patients receiving IVIg, there have been reports of acute non-cardiogenic pulmonary edema(Transfusion Related Acute Lung Injury, (TRALI) in patients administered IVIg (including KIOVIG).

TRALI is characterised by severe hypoxia, dyspnoea, tachypnoea, cyanosis, fever and hypotension.

Symptoms of TRALI typically develop during or within 6 hours of a transfusion, often within 1-2hours. Therefore, IVIg recipients must be monitored for and IVIg infusion must be immediatelystopped in case of pulmonary adverse reactions. TRALI is a potentially lifethreatening conditionrequiring immediate intensive-care-unit management.

Aseptic meningitis syndrome (AMS)

Aseptic meningitis syndrome has been reported to occur in association with IVIg treatment. Thesyndrome usually begins within several hours to 2 days following IVIg treatment. 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 mayoccur more frequently in association with high-dose (2 g/kg) IVIg treatment.

Patients exhibiting such signs and symptoms should receive a thorough neurological examination,including CSF studies, to rule out other causes of meningitis.

Discontinuation of IVIg treatment has resulted in remission of AMS within several days withoutsequelae.

From post-marketing data with KIOVIG no clear correlation of AMS to higher doses was observed.

Higher incidences of AMS were seen in women.

Haemolytic anaemia

IVIg products can contain blood group antibodies that may act as haemolysins and induce in vivocoating of red blood cells with immunoglobulin, causing a positive direct antiglobulin reaction(Coombs' test) and, rarely, haemolysis. Haemolytic anaemia can develop subsequent to IVIg therapydue to enhanced red blood cells (RBC) sequestration. IVIg recipients should be monitored for clinicalsigns and symptoms of haemolysis. (See section 4.8.)

Neutropenia/Leukopenia

A transient decrease in neutrophil count and/or episodes of neutropenia, sometimes severe, have beenreported after treatment with IVIgs. This typically occurs within hours or days after IVIgadministration and resolves spontaneously within 7 to 14 days.

Interference with serological testing

After infusion of immunoglobulin 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 antigens, e.g. A, B, D, may interfere with someserological tests for red cell antibodies, for example the direct antiglobulin test (DAT, direct

Coombs’ test).

Administration of KIOVIG can lead to false positive readings in assays that depend on detection ofbeta-D-glucans for diagnosis of fungal infections. This may persist during the weeks followinginfusion of the product.

Transmissible agents

KIOVIG is made from human plasma. Standard measures to prevent infections resulting from the useof medicinal products prepared from human blood or plasma include selection of donors, screening ofindividual donations and plasma pools for specific markers of infection and the inclusion of effectivemanufacturing steps for the inactivation/removal of viruses. Despite this, when medicinal productsprepared from human blood or plasma are administered, the possibility of transmitting 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 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

B19 transmission with immunoglobulins and it is also assumed that the antibody content makesan important contribution to the viral safety.

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

There are no paediatric specific risks with regard to any of the above adverse events. Paediatricpatients may be more susceptible to volume overload (see Section 4.9).

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 product, an interval of 3 months should elapse before vaccination with liveattenuated 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.

Dilution of KIOVIG with a 5% glucose solution may result in increased blood glucose levels.

Loop diuretics

Avoidance of concomitant use of loop diuretics.

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 trials and therefore it should only be given with caution to pregnant women and breast-feedingmothers. IVIg products have been shown to cross the placenta, increasingly during the third trimester.

Clinical experience with immunoglobulins suggests that no harmful effects on the course ofpregnancy, or on the foetus and the neonate are to be expected.

Immunoglobulins are excreted into the milk and may contribute to protecting the neonate frompathogens which have a mucosal portal of entry. No negative effects on the breastfed newborn/infantsare anticipated.

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

The ability to drive and operate machines may be impaired by some adverse reactions associated with

KIOVIG. Patients who experience adverse reactions during treatment should wait for these to resolvebefore driving or operating machines.

Adverse reactions such as chills, headache, dizziness, fever, vomiting, allergic reactions, nausea,arthralgia, low blood pressure and moderate low back pain may occur occasionally.

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

Cases of reversible aseptic meningitis and rare cases of transient cutaneous reactions (includingcutaneous lupus erythematosus - frequency unknown) have been observed with human normalimmunoglobulin. Reversible haemolytic reactions have been observed in patients, especially thosewith blood groups A, B, and AB. Rarely, haemolytic anaemia requiring transfusion may develop afterhigh dose IVIg treatment (see also Section 4.4).

Increase in serum creatinine level and/or acute renal failure have been observed.

Very rarely: Thromboembolic reactions such as myocardial infarction, stroke, pulmonary embolism,and deep vein thromboses.

Cases of Transfusion Related Acute Lung Injury (TRALI).

The tables presented below are according to the MedDRA system organ classification (SOC and

Preferred Term Level). Table 1 shows the adverse reactions from clinical trials and Table 2 shows thepost-marketing ARs.

Frequencies have been evaluated according to 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, adverse reactions are presented in order of decreasing seriousness.

Table 1

Frequency of Adverse Reactions (ADRs) in clinical studies with KIOVIG

MedDRA

System Organ Class Adverse reaction Frequency(SOC)

Infections and infestations Bronchitis, nasopharyngitis Common

Chronic sinusitis, fungal infection, infection, kidney Uncommoninfection, sinusitis, upper respiratory tract infection,urinary tract infection, bacterial urinary tract infection,meningitis aseptic

Blood and lymphatic Anaemia, lymphadenopathy Commonsystem disorders

Immune system disorders Hypersensitivity, anaphylactic reaction Uncommon

Endocrine disorders Thyroid disorder Uncommon

Metabolism and nutrition Decreased appetite Commondisorders

Psychiatric disorders Insomnia, anxiety Common

Irritability Uncommon

Nervous system disorders Headache Very common

Dizziness, migraine, paresthesia, hypoesthesia Common

Table 1

Frequency of Adverse Reactions (ADRs) in clinical studies with KIOVIG

MedDRA

System Organ Class Adverse reaction Frequency(SOC)

Amnesia, dysarthria, dysgeusia, balance disorder, Uncommontremor

Eye disorders Conjunctivitis Common

Eye pain, eye swelling Uncommon

Ear and labyrinth Vertigo, fluid in middle ear Uncommondisorders

Cardiac disorders Tachycardia Common

Vascular disorders Hypertension Very common

Flushing Common

Peripheral coldness, phlebitis Uncommon

Respiratory, thoracic and Cough, rhinorrhoea, asthma, nasal congestion, Commonmediastinal disorders oropharyngeal pain, dyspnea

Oropharyngeal swelling Uncommon

Gastrointestinal disorders Nausea Very common

Diarrhoea, vomiting, abdominal pain, dyspepsia Common

Abdominal distension Uncommon

Skin and subcutaneous Rash Very commontissue disorders Contusion, pruritus, urticaria, dermatitis, erythema Common

Angioedema, acute urticaria, cold sweat, Uncommonphotosensitivity reaction, night sweats, hyperhidrosis

Musculoskeletal and Back pain, arthralgia, pain in extremity, myalgia, Commonconnective tissue muscle spasms, muscular weaknessdisorders Muscle twitching Uncommon

Renal and urinary Proteinuria Uncommondisorders

General disorders and Local reactions (e.g. infusion site Very commonadministration site pain/swelling/reaction/pruritus), pyrexia, fatigueconditions Chills, edema, influenza-like illness, chest discomfort, Commonchest pain, asthenia, malaise, rigors

Chest tightness, feeling hot, burning sensation, Uncommonswelling

Investigations Blood cholesterol increased, blood creatinine Uncommonincreased, blood urea increased, white blood cellcount decreased, alanine aminotransferase increased,haematocrit decreased, red blood cell count decreased,respiratory rate increased

Table 2

Post-Marketing Adverse Reactions (ARs)

MedDRA

System Organ Class Adverse reaction Frequency(SOC)

Blood and lymphatic Haemolysis Not knownsystem disorders

Immune system disorders Anaphylactic shock Not known

Nervous system disorders Transient ischemic attack, cerebral vascular accident Not known

Cardiac disorders Myocardial infarction Not known

Vascular disorders Hypotension, deep vein thrombosis Not known

Respiratory, thoracic and Pulmonary embolism, pulmonary edema Not knownmediastinal disorders

Table 2

Post-Marketing Adverse Reactions (ARs)

MedDRA

System Organ Class Adverse reaction Frequency(SOC)

Investigations Coombs direct test positive, oxygen saturation Not knowndecreased

Injury, poisoning and Transfusion-related acute lung injury Not knownprocedural complications

Muscle twitching and weakness were reported only in patients with MMN.

Frequency, type and severity of adverse reactions in children are the same as in adults.

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.

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

Overdose may lead to fluid overload and hyperviscosity, particularly in patients at risk, includingelderly patients or patients with cardiac or renal impairment (see section 4.4 ).

Smaller children below the age of 5 years may be particularly susceptible to volume overload.

Therefore, dosing should be carefully calculated for this population. In addition, children with

Kawasaki Disease are at especially high risk due to underlying cardiac compromise so dose and rateof administration should be carefully controlled.

Pharmacotherapeutic group: immune sera and immunoglobulins: immunoglobulins, normal human,for intravascular administration, ATC code: J06BA02

Human normal immunoglobulin contains mainly immunoglobulin G (IgG) with a broad spectrumof antibodies 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 1000 donations. It has a distribution ofimmunoglobulin G subclasses closely proportional to that in native human plasma. Adequate dosesof this medicinal product may restore abnormally low immunoglobulin G levels to the normal range.

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

There are no theoretical or observed differences in the action of immunoglobulins in childrencompared to adults.

Human normal immunoglobulin is immediately and completely bioavailable in the recipient’scirculation after intravenous administration. It is distributed relatively rapidly between plasma andextravascular fluid; after approximately 3 to 5 days equilibrium is reached between the intra- andextravascular compartments.

Pharmacokinetic parameters for KIOVIG were determined in the two clinical studies in PID patientsperformed in Europe and the US. In these studies, a total of 83 subjects at least 2 years of age weretreated with doses of 300 to 600 mg/kg body weight every 21 to 28 days for 6 to 12 months. Themedian IgG half-life after administration of KIOVIG was 32.5 days. This half-life may vary frompatient to patient, in particular in primary immunodeficiency. Pharmacokinetic parameters for theproduct are summarized in the table below. All parameters were analysed separately for three agegroups, children (below 12 years, n=5), adolescents (13 to 17 years, n=10), and adults (above 18 yearsof age, n=64). The values obtained in the studies are comparable to parameters reported for otherhuman immunoglobulins.

Summary of KIOVIG pharmacokinetic parameters

Children Adolescents Adults

Parameter (12 years or below) (13 to 17 years) (18 years or above)

Median 95% CI* Median 95% CI Median 95% CI

Terminal half-life (days) 41.3 20.2 to 86.8 45.1 27.3 to 89.3 31.9 29.6 to 36.1

Cmin (mg/dl)/(mg/kg)2.28 1.72 to 2.74 2.25 1.98 to 2.64 2.24 1.92 to 2.43(trough level)

Cmax (mg/dl)/(mg/kg)4.44 3.30 to 4.90 4.43 3.78 to 5.16 4.50 3.99 to 4.78(peak level)

In-vivo recovery (%) 121 87 to 137 99 75 to 121 104 96 to 114

Incremental recovery2.26 1.70 to 2.60 2.09 1.78 to 2.65 2.17 1.99 to 2.44(mg/dl)/(mg/kg)

AUC0-21d (g·h/dl)1.49 1.34 to 1.81 1.67 1.45 to 2.19 1.62 1.50 to 1.78(area under the curve)

*CI - Confidence Interval

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

Immunoglobulins are normal constituents of the human body.

The safety of KIOVIG 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.

Studies of repeated dose toxicity, genotoxicity, and toxicity to reproduction in animals areimpracticable due to induction of and interference by developing antibodies to heterologous proteins.

Since clinical experience provides no evidence for carcinogenic potential of immunoglobulins,no experimental studies in heterogeneous species were performed.

Glycine

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts, nor with any other IVIg products.

2 years.

If dilution to lower concentrations is required, immediate use after dilution is recommended.

The in-use stability of KIOVIG after dilution with a 5% glucose solution to a final concentrationof 50 mg/ml (5%) immunoglobulin has been demonstrated for 21 days at 2°C to 8°C as well as 28°Cto 30°C; however, these studies did not include the microbial contamination and safety aspect.

Do not store above 25°C.

Do not freeze.

Keep the vial in the outer carton in order to protect from light.

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

10, 25, 50, 100, 200 or 300 ml of solution in a vial (Type I glass) with a stopper (bromobutyl).

Pack size: 1 vial

Not all presentations may be marketed.

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

If dilution is required, 5% glucose solution is recommended. For obtaining an immunoglobulinsolution of 50 mg/ml (5%), KIOVIG 100 mg/ml (10%) should be diluted with an equal volumeof the glucose solution. It is recommended that during dilution the risk of microbial contaminationis minimised.

The product should be inspected visually for particulate matter and discolouration prior toadministration. The solution should be clear or slightly opalescent and colourless or pale yellow.

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

KIOVIG should only be administered intravenously. Other routes of administration have not beenevaluated.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Takeda Manufacturing Austria AG

Industriestrasse 67

A-1221 Vienna, AustriamedinfoEMEA@takeda.com

EU/1/05/329/001

EU/1/05/329/002

EU/1/05/329/003

EU/1/05/329/004

EU/1/05/329/005

EU/1/05/329/006

Date of first authorization: 19 January 2006

Date of latest renewal: 06 December 2010

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

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