CINRYZE 500UI powder + solvent for injection medication leaflet

Cinryze 500 IU powder and solvent for solution for injection

Each single-use powder vial contains 500 International Units (IU) of human C1-esterase inhibitorproduced from the plasma of human donors.

After reconstitution, one vial contains 500 IU of human C1-esterase inhibitor per 5 ml correspondingto a concentration of 100 IU/ml. One IU is equivalent to the amount of C1-esterase inhibitor present in1 ml of normal human plasma.

The total protein content of the reconstituted solution is 15 ± 5 mg/ml.

Each vial of Cinryze contains approximately 11.5 mg of sodium.

For the full list of excipients, see section 6.1.

Powder and solvent for solution for injection.

White powder.

The solvent is a clear, colourless solution.

Treatment and pre-procedure prevention of angioedema attacks in adults, adolescents and children(2 years old and above) with hereditary angioedema (HAE).

Routine prevention of angioedema attacks in adults, adolescents and children (6 years old and above)with severe and recurrent attacks of hereditary angioedema (HAE), who are intolerant to orinsufficiently protected by oral prevention treatments, or patients who are inadequately managed withrepeated acute treatment.

Cinryze therapy should be initiated under supervision of a physician experienced in the care ofpatients with hereditary angioedema (HAE).

Treatment of angioedema attacks

- 1 000 IU of Cinryze at the first sign of the onset of an angioedema attack.

- A second dose of 1 000 IU may be administered if the patient has not responded adequatelyafter 60 minutes.

- For patients experiencing laryngeal attacks or if initiation of treatment is delayed, the seconddose can be given sooner than 60 minutes.

Routine prevention of angioedema attacks

- 1 000 IU of Cinryze every 3 or 4 days is the recommended starting dose for routine preventionagainst angioedema attacks; the dosing interval may need to be adjusted according to individualresponse. The continued need for regular prophylaxis with Cinryze should be reviewed on aregular basis.

Pre-procedure prevention of angioedema attacks

- 1 000 IU of Cinryze within 24 hours before a medical, dental or surgical procedure.

For treatment, routine prevention and pre-procedure prevention in adolescents 12 to 17 years old, thedose is the same as for adults.

The safety and efficacy of Cinryze in children less than 2 years old has not been established. Datasupporting dosing recommendations in children less than 6 years old are very limited. Currentlyavailable data are described in sections 4.8, 5.1 and 5.2.

Treatment of angioedema Pre-procedure prevention of Routine prevention ofattacks angioedema attacks angioedema attacks2 to 11 years, > 25 kg: 2 to 11 years, > 25 kg: 6 to 11 years:1 000 IU of Cinryze at the first 1 000 IU of Cinryze within 500 IU of Cinryze everysign of the onset of an acute 24 hours before a medical, 3 or 4 days is the recommendedattack. dental, or surgical procedure. starting dose for routineprevention against angioedema

A second dose of 1 000 IU may attacks. The dosing intervalbe administered if the patient and dose may need to behas not responded adequately adjusted according toafter 60 minutes. individual response. Thecontinued need for regular2 to 11 years, 10 - 25 kg: 2 to 11 years, 10 - 25 kg: prophylaxis with Cinryze500 IU of Cinryze at the first 500 IU of Cinryze within should be reviewed on asign of the onset of an acute 24 hours before a medical, regular basis.attack. dental, or surgical procedure.

A second dose of 500 IU maybe administered if the patienthas not responded adequatelyafter 60 minutes.

No special investigations have been performed. For treatment, routine prevention and pre-procedureprevention in elderly patients, 65 years of age or older, the dose is the same as for adults.

No special investigations have been performed. For treatment, routine prevention and pre-procedureprevention in patients with renal or hepatic impairment, the dose is the same as for adults.

For intravenous use only.

The reconstituted product should be administered by intravenous injection at a rate of 1 ml per minute.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

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

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

Thrombotic events have been reported in neonatal and infant subjects undergoing cardiac bypassprocedures while receiving off-label high doses of another C1-esterase inhibitor product (up to500 Units()/kg) to prevent capillary leak syndrome. Based upon an animal study there is a potentialthrombogenic threshold at doses greater than 200 Units()/kg. Patients with known risk factors forthrombotic events (including indwelling catheters) should be monitored closely.() [Historically assigned potency values were relative to an in-house reference standard whereby 1 Unit (U) isequal to the mean quantity of C1-esterase inhibitor present in 1 ml of normal human plasma.] An internationalreference standard (IU) has now been implemented where IU is also defined as the amount of C1-esteraseinhibitor present in 1 ml of normal human plasma.

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.

Appropriate vaccination (hepatitis A and B) should be considered for patients in regular/repeatedreceipt of human plasma-derived C1-esterase inhibitor product.

As with any biological product hypersensitivity reactions may occur. Hypersensitivity reactions mayhave symptoms similar to angioedema attacks. Patients should be informed of the early signs ofhypersensitivity reactions including hives, generalised urticaria, tightness of the chest, wheezing,hypotension and anaphylaxis. If these symptoms occur after administration, they should alert theirphysician. In case of anaphylactic reactions or shock, emergency medical treatment should beadministered.

Home-treatment and self-administration

There are limited data on the use of this medicinal product in home- or self-administration. Potentialrisks associated with home-treatment are related to the administration itself as well as the handling ofadverse reactions, particularly hypersensitivity. The decision on the use of home-treatment for anindividual patient should be made by the treating physician, who should ensure that appropriatetraining is provided, and the use reviewed at intervals.

Thrombotic events have been reported in neonatal and infant subjects undergoing cardiac bypassprocedures while receiving off-label high doses of another C1-esterase inhibitor product (up to500 Units()/kg) to prevent capillary leak syndrome.

This medicinal product contains 11.5 mg sodium per vial, equivalent to 0.5 % of the WHOrecommended maximum daily intake of 2 g sodium for an adult.

No interaction studies have been performed.

Human C1-esterase inhibitor is a physiological component of human plasma. Therefore, no adverseeffects on fertility, pre- and post-natal development are expected in humans.

Animal-reproductive studies show no maternal or embryofoetal effects in rats at dose levels up to28-times the recommended human dose (1 000 IU) based on an average adult body weight of 70 kg.

Data on a limited number of exposed pregnancies are available from clinical studies and from post-marketing experience (including data from two observational studies) and indicate no adverse effectsof human C1-esterase inhibitor on pregnancy or on the health of the foetus/newborn child(see section 5.1).

Cinryze should be given to pregnant women only if clearly indicated.

It is unknown whether human C1-esterase inhibitor is excreted in human milk. A risk to thenewborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feedingor to discontinue/abstain from Cinryze therapy taking into account the benefit of breast-feeding for thechild and the benefit of therapy for the woman.

No specific studies on fertility, early embryonic and postnatal development, or carcinogenicity studieswere conducted (see section 5.3).

Based upon the clinical data currently available, Cinryze has minor influence on the ability to driveand use machines.

The very common adverse reactions observed following Cinryze infusion in clinical studies wereheadache and nausea.

Adverse reaction frequencies were estimated from 2 pivotal placebo-controlled and 2 open-labelstudies in 251 unique subjects. Only frequencies based on reporting rates from clinical trials are usedto assign frequency category.

Adverse reactions to treatment with Cinryze are classified by MedDRA System Organ Class andabsolute frequency in Table 1. Within each frequency grouping, adverse reactions are presented inorder of decreasing seriousness. Frequencies are defined as 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), and not known (cannot be estimated from the available data).

Table 1 Adverse reactions reported in clinical studies and in post marketing reports

System Organ Class Frequency Adverse reaction

Immune system disorders Common Hypersensitivity

Metabolism and nutrition disorders Uncommon Hyperglycaemia

Very common Headache

Common Dizziness

Venous thrombosis, phlebitis, venous

Vascular disorders Uncommonburning, hot flush

Respiratory, thoracic and mediastinal

Uncommon Coughdisorders

Very common Nausea

Gastrointestinal disorders Common Vomiting

Uncommon Diarrhoea, abdominal pain

Skin and subcutaneous tissue Common Rash, erythema, pruritusdisorders Uncommon Contact dermatitis

Musculoskeletal and connective tissue

Uncommon Joint swelling, arthralgia, myalgiadisorders

Injection site rash/erythema, infusion

General disorders and administration Commonsite pain, pyrexiasite conditions

Uncommon Chest discomfort

Among reports of venous thrombosis, the most common underlying risk factor was presence of anindwelling catheter.

Local reactions at the injection site were uncommon. In clinical studies local reactions (described aspain, bruising, or rash at the injection/catheter site, venous burning or phlebitis) occurred inassociation with approximately 0.2 % of infusions.

Across clinical studies, there were 61 unique paediatric subjects enrolled and exposed to over2 500 infusions of Cinryze (2 - 5 years, n = 3; 6 - 11 years, n = 32; 12 - 17 years, n = 26). Amongthese children, the only adverse reactions with Cinryze included headache, nausea, pyrexia, andinfusion site erythema. None of these adverse reactions were severe, and none led to discontinuationof medicinal product.

Overall, the safety and tolerability of Cinryze are similar in children, adolescents and adults.

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

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

No case of overdose has been reported.

Pharmacotherapeutic group: Drugs used in hereditary angioedema, C1-esterase inhibitor, plasmaderived, ATC code: B06AC01.

C1-esterase inhibitor is a member of the serine protease inhibitor, or serpin, superfamily of proteins.

The main function of serpins is to regulate the activity of serine proteases. C1-esterase inhibitor is asingle chain glycoprotein found in plasma which, in its mature state, consists of 478 amino acids withan apparent molecular weight of 105 kD.

C1-esterase inhibitor inhibits the complement system by binding C1r and C1s, two of the activeenzyme subunits of the first component of the complement system (C1) in the classical pathway, aswell as to mannose-binding lectin-associated serine proteases in the lectin pathway. The primarysubstrate of the activated C1 enzyme is C4; uninhibited C1 results in diminished C4 levels. C1 is themost important inhibitor of contact activation and regulates the contact system and the intrinsiccoagulation pathway by binding to and inactivating kallikrein and factor XIIa. Because these pathwaysare part of enzyme amplification cascades, without C1-esterase inhibitor, spontaneous ortrigger-induced activation of these pathways can lead to unopposed activation and swelling.

In clinical studies, the intravenous administration of Cinryze resulted in a significant increase insystemic levels of antigenic and functional C1-esterase inhibitor within 1 hour after administration.

Administration of C1-esterase inhibitor increases serum levels of C1-esterase inhibitor activity andtemporarily restores the natural regulation of the contact, complement, and fibrinolytic systemsthereby controlling the swelling or the propensity to swell.

Low serum C4 levels often correlate with HAE attacks. Treatment with Cinryze resulted in elevationof C4 levels at 12 hours. There was a statistically significant (p = 0.0017) difference in the changes inmean values from baseline between treatment groups at 12 hours, demonstrating the association of

Cinryze treatment with an increase in C4 activity (Cinryze + 2.9 mg/dl versus placebo + 0.1 mg/dl).

Data from two randomised, double-blind, placebo-controlled studies (LEVP 2005-1/A and

LEVP 2005-1/B), data from two open-label studies (LEVP 2006-1 and LEVP 2006-4) and 2 paediatricclinical studies (0624-203 and 0624-301) demonstrated the efficacy of Cinryze for the treatment andprevention of angioedema attacks in subjects with HAE.

Data from two observational studies (SHP616-401, IOS) that included subjects aged 8 to 83 yearswere consistent with the existing safety profile and no new safety concerns have been identifiedfollowing exposure to Cinryze.

Cinryze for the treatment of HAE attacks

Study LEVP 2005-1/A used a randomised, double-blind, placebo-controlled, parallel group design;71 subjects with acute HAE attacks were randomised (36 Cinryze, 35 placebo). The studydemonstrated that treatment with Cinryze within 4 hours after the onset of an HAE attack resulted in agreater than 2-fold decrease in the time to beginning of unequivocal relief of the defining symptom ofthe HAE attack compared to placebo (median 2 hours for Cinryze vs. > 4 hours for placebo,p = 0.048). Treatment with Cinryze also resulted in a greater than 2-fold decrease in the time tocomplete resolution of the HAE attack compared to placebo (median 12.3 hours vs. 31.6 hours,p = 0.001). The percentage of subjects with beginning of unequivocal relief of the defining symptomwithin 4 hours after dosing was 60 % for Cinryze and 42 % for placebo (p = 0.062). Among15 subjects treated with open-label Cinryze for laryngeal HAE attacks, none required intubation.

In open-label study LEVP 2006-1, 101 subjects were treated for a total of 609 acute HAE attacks(median 3 attacks per subject; range: 1 - 57). Within 4 hours after Cinryze dosing, 87 % of attacksachieved unequivocal relief of the defining symptom. For 95 % of attacks, clinical relief was observedand/or subjects were discharged to home within 4 hours. For subjects with > 1 attack, the proportion ofattacks responding within 4 hours after Cinryze dosing and the time to response was comparableregardless of the number of attacks treated. Among 84 separate laryngeal HAE attacks, none requiredintubation following treatment with Cinryze.

Cinryze for the routine prevention of HAE attacks

Study LEVP 2005-1/B used a randomised, double-blind, placebo-controlled, crossover design;22 subjects were evaluable for efficacy (randomised and treated in both crossover periods). The studydemonstrated that prophylaxis with Cinryze resulted in a greater than 2-fold reduction in the numberof HAE attacks compared to placebo (mean 6.3 attacks for Cinryze vs. 12.8 attacks for placebo,p < 0.0001). Angioedema attacks were also less severe during prophylactic Cinryze therapy comparedto placebo (mean severity score 1.3 vs. 1.9 or a 32 % reduction, p = 0.0008) and of shorter duration(mean 2.1 days vs. 3.4 days or a 38 % reduction, p = 0.0004). The total number of days of swellingduring prophylactic Cinryze therapy was reduced compared to placebo (mean 10.1 days vs. 29.6 daysor a 66 % reduction, p < 0.0001). In addition, fewer open-label Cinryze infusions were required fortreatment of HAE attacks during therapy with Cinryze compared to placebo (mean 4.7 infusions vs.15.4 infusions or 70 % reduction, p < 0.0001).

In open-label study LEVP 2006-4, 146 subjects received Cinryze as HAE prophylaxis for periodsranging from 8 days to approximately 32 months (median 8 months). Prior to enrolment, subjectsreported a median monthly HAE attack rate of 3.0 (range: 0.08 - 28.0); during therapy withprophylactic Cinryze, this rate was 0.21 (range: 0 - 4.56), and 86 % of subjects experienced anaverage of ≤ 1 attack per month. For subjects receiving Cinryze prophylaxis for at least 1 year, themonthly attack rate per subject remained consistently low (0.34 attacks per month) relative to pre-study rates.

Cinryze for the pre-procedure prevention of HAE attacks

Open-label Cinryze was administered within 24 hours prior to a total of 91 medical, dental, or surgicalprocedures across the clinical programme (40 procedures in children and 51 procedures in adults). For98 % of procedures, no HAE attacks were reported within the 72 hours after the Cinryze dose.

Paediatric population (age-group 6 - 11 years)

Cinryze for the treatment of HAE attacks

Study LEVP 2006-1: Twenty-two paediatric subjects were treated for 121 acute HAE attacks. Theproportion of HAE attacks achieving unequivocal relief of the defining symptom within 4 hours after

Cinryze treatment was comparable between the 22 children enrolled (age range: 2 - 17) and adults,with 89 % and 86 % of attacks achieving relief, respectively.

Study 0624-203: Nine subjects (age range: 6 - 11) were enrolled and received a single dose of

Cinryze: 3 subjects (10 - 25 kg) received 500 Units(); 3 subjects (> 25 kg) 1 000 Units(), and3 subjects (> 25 kg) 1 500 Units(). All 9 (100 %) subjects achieved unequivocal beginning of relief ofthe defining symptom within 4 hours following initiation of treatment with Cinryze. Median intervalwas 0.5 hours (range: 0.25 - 2.5 hours): 1.25, 0.25, and 0.5 hours in the 500 Units(), 1 000 Units(),and 1 500 Units() Cinryze groups, respectively. Median interval to complete resolution of the HAEattack for the 9 subjects was 13.6 hours (range: 1.6 - 102.3 hours).

Cinryze for the prevention of HAE attacks

Study LEVP 2006-4: Prior to enrollment, 23 children (age range: 3 to 17 years) reported a medianmonthly HAE attack rate of 3.0 (range: 0.5 - 28.0). During the study while receiving Cinryzeprophylaxis (1 000 Units() every 3 to 7 days; with the exception of a 3 year old child, receiving500 Units() every 3 to 7 days), children in the various age subgroups experienced median monthly

HAE attack rates of 0.4 (range: 0 - 3.4), and 87 % of children reported an average of ≤ 1 attack permonth; these results were comparable to those observed in adults.

Study 0624-301: Six pediatric subjects (6 to 11 years of age) were enrolled and randomised to twiceweekly dosing for 12 weeks in 2 treatment sequences (500/1 000 Units() or 1 000/500 Units()

Cinryze). Both doses resulted in similar reduction of attack-frequency and showed clinical benefitregarding severity, duration, and requirement for acute treatment of attacks.

Paediatric population (age-group < 6 years)

For the 3 subjects less than 6 years, administration of Cinryze (500 Units() or 1 000 Units()) wasassociated with increases in C1-esterase inhibitor levels and clinical efficacy in acute treatment andprevention of attacks. Overall administration of Cinryze was well tolerated.

In all studies, administration of Cinryze resulted in increases in antigenic and functional C1-esteraseinhibitor levels post-infusion compared to pre-infusion values in both children and adults.

A randomised, parallel group, open-label pharmacokinetic study of Cinryze was performed in subjectswith non-symptomatic HAE. The subjects received either a single intravenous dose of 1 000 Units()or a 1 000 Units() dose followed by a second dose of 1 000 Units() 60 minutes later. The meanpharmacokinetic parameters for functional human C1-esterase inhibitor derived frombaseline-corrected concentration data are presented in Table 2.

Table 2 Mean Pharmacokinetic Parameters for Functional C1-esterase inhibitor Following

Administration of Cinryze

Double Dose

Single Dose (1 000 Units dose followed by a

Parameters(1 000 Units*) second 1 000 Units dose 60 minuteslater)

Cbaseline (U/ml) 0.31 ± 0.20 (n = 12) 0.33 ± 0.20 (n = 12)

Cmax (U/ml) 0.68 ± 0.08 (n = 12) 0.85 ± 0.12 (n = 13)

Baseline-corrected Cmax (U/ml) 0.37 ± 0.15 (n = 12) 0.51 ± 0.19 (n = 12)tmax (hr) [median (range)] [1.2 (0.3 - 26.0)] (n = 12) [2.2 (1.0 - 7.5)] (n = 13)

AUC(0-t) (U*hr/ml) 74.5 ± 30.3 (n = 12) 95.9 ± 19.6 (n = 13)

Baseline-corrected AUC(0-t) 24.5 ± 19.1 (n = 12) 39.1 ± 20.0 (n = 12)(U*hr/ml)

CL (ml/min) 0.85 ± 1.07 (n = 7) 1.17 ± 0.78 (n = 9)

Elimination half-life (hr) 56 ± 35 (n = 7) 62 ± 38 (n = 9)n = number of subjects evaluated.

* Historically assigned potency values are expressed in in-house Units (U).

After intravenous administration of a single dose of Cinryze to HAE subjects, the serum concentrationof functional C1-esterase inhibitor doubled within 1 to 2 hours. The maximum serum concentration(Cmax) and area under the serum concentration-time curve (AUC) appeared to increase from the singleto double dose, although the increase was not dose-proportional. The mean elimination half-life offunctional C1-esterase inhibitor after administration of Cinryze was 56 hours for a single dose and62 hours for the double dose.

Because C1-esterase inhibitor is an endogenous human plasma protein, it is not subject to metabolismby Cytochrome P450 iso-enzymes, excretion, or pharmacokinetic drug-drug interactions exhibited bymany low molecular weight compounds. The expected consequence of metabolism of a glycoproteinis via degradation to small peptides and individual amino acids. As such, the pharmacokinetics andexcretion of Cinryze are not expected to be altered by renal or hepatic impairment.

Functional C1-esterase inhibitor activity was measured in children in the two open label studies(see section 5.1). Mean increases from baseline in functional C1-esterase inhibitor activity measured1 hour post-dose in children 2 to < 18 years of age ranged from 20 % to 88 % in Study LEVP 2006-1(treatment) and from 22 % to 46 % in Study LEVP 2006-4 (prevention) compared with 21 % to 66 %and 25 % to 32 % in adults, respectively. Two additional studies evaluated plasma levels in children(6 - 11 years).

In study 624-203, plasma C1-esterase inhibitor antigen and functional activity from 9 patients wereobtained following a single IV dose of 500 Units(), 1 000 Units(), or 1 500 Units() Cinryze based onbody weight (see section 5.1). Increases in C1-esterase inhibitor antigen levels and functional activityabove the baseline values at 1 hour and 24 hours post-dose were demonstrated.

In Study 0624-301, plasma C1-esterase inhibitor antigen and functional activity were measured from6 patients pre-dose and 1 h following IV administration of two dose levels of Cinryze (500 Units()and 1 000 Units()) every 3 or 4 days for 12 weeks. Both Cinryze doses resulted in relevant plasmalevels of C1-esterase inhibitor antigen and functional activity.

Cinryze contains as active ingredient C1-esterase inhibitor. It is derived from human plasma and actslike an endogenous constituent of plasma.

Non-clinical data reveal no special hazard for humans based on conventional studies of generaltoxicity and toxicity to reproduction. No genotoxicity studies were performed as the active substanceis unlikely to interact directly with DNA or other chromosomal material. No studies on fertility, earlyembryonic and post-natal development, or carcinogenicity studies were conducted because chronicdosing in animals would be expected to be associated with development of neutralising antibodies tothe human protein.

Sodium chloride

Sucrose

Sodium citrate

L-valine

L-alanine

L-threonine

Water for injections

Only use a silicone-free syringe (provided in the pack) for administration of the product.

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

2 years.

After reconstitution, the product should be used immediately. However, chemical and physical in-usestability has been demonstrated for 3 hours at room temperature (15 °C - 25 °C).

Store below 25 °C. Do not freeze. Store in the original package in order to protect from light.

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

500 IU of human C1-esterase inhibitor in a colourless glass vial (Type I), closed with a rubber stopper(Type I) and an aluminium seal with a plastic flip-off cap.

5 ml of water for injections in a colourless glass vial (Type I), closed with a rubber stopper (Type I)and an aluminium seal with a plastic flip-off cap.

Each pack contains:

Two powder vials.

Two solvent vials.2 filter transfer devices, 2 disposable 10 ml syringes, 2 venipuncture sets, and 2 protective mats.

Each kit contains material for either one 1 000 IU dose or two 500 IU doses.

Reconstitution and administration of Cinryze

Reconstitution, product administration and handling of the administration set and needles must bedone with caution.

Use either the filter transfer device provided with Cinryze or a commercially available double-endedneedle.

Preparation and handling

Cinryze is intended for intravenous administration after reconstitution with water for injections.

Cinryze vial is for single use only.

One powder vial, 1 solvent vial, 1 filter transfer device, 1 disposable 10 ml syringe, 1 venipuncture setand 1 protective mat is needed to prepare one dose of 500 IU.

Two powder vials, 2 solvent vials, 2 filter transfer devices, 1 disposable 10 ml syringe, 1 venipunctureset and 1 protective mat is needed to prepare one dose of 1 000 IU.

Each product vial should be reconstituted with 5 ml water for injections.

One vial of reconstituted Cinryze corresponds to a dose of 500 IU.

Two vials of reconstituted Cinryze correspond to a dose of 1 000 IU. Therefore, two vials arecombined for one dose of 1 000 IU.

1. Work on the mat provided and wash your hands before performing the following procedures.2. Aseptic technique should be used during the reconstitution procedure.3. Ensure the powder vial and the solvent vial are at room temperature (15 ºC - 25 ºC).4. Release the powder vial label by peeling down the purple strip indicated by the arrow.5. Remove plastic caps from the powder and solvent vials.6. Cleanse stoppers with a disinfection swab and allow them to dry prior to use.7. Remove protective covering from the top of the transfer device package. Do not remove thedevice from the package.8. Note: the transfer device must be attached to the solvent vial before being attached to thepowder vial, so that the vacuum in the powder vial is not lost. Place the solvent vial on a flatsurface and insert the blue end of the transfer device into the solvent vial, pushing down untilthe spike penetrates through the centre of the solvent vial stopper and the device snaps in place.

The transfer device must be vertical prior to penetrating the stopper closure.

9. Remove the plastic package from the transfer device and discard it. Take care not to touch theexposed end of the transfer device.

10. Place the powder vial on a flat surface. Invert the transfer device and the solvent vial containingwater for injections and insert the clear end of the transfer device into the powder vial, pushingdown until the spike penetrates the rubber stopper and the transfer device snaps into place. Thetransfer device must be vertical prior to penetrating the stopper closure of the powder vial. Thevacuum in the powder vial will draw in the solvent. If there is no vacuum in the vial, do not usethe product.

11. Gently swirl the powder vial until all powder is dissolved. Do not shake the powder vial. Makesure all the powder is completely dissolved.

12. Disconnect the solvent vial by turning it anti-clockwise. Do not remove the clear end of thetransfer device from the powder vial.

One vial of reconstituted Cinryze contains 500 IU of human C1-esterase inhibitor in 5 ml, resulting ina concentration of 100 IU/ml. Proceed to administration process if patients receive a dose of 500 IU.

Two vials of Cinryze powder must be reconstituted to make one dose (1 000 IU/10 ml). Therefore,repeat instructions 1 to 12 above using an additional package containing a transfer device toreconstitute the second of two powder vials. Do not reuse the transfer device. Once the two vials arereconstituted proceed to administration process for a dose of 1 000 IU.

Administration process for a dose of 500 IU1. Aseptic technique should be used during the administration procedure.2. After reconstitution, the Cinryze solutions are colourless to slightly blue and clear. Do not usethe product if the solutions are turbid or discoloured.3. Using a sterile, disposable 10 ml syringe, draw back the plunger to allow approximately 5 ml ofair into the syringe.4. Attach the syringe onto the top of the clear end of the transfer device by turning it clockwise.5. Invert the vial gently and inject air into the solution and then slowly withdraw the reconstituted

Cinryze solution into the syringe.6. Detach the syringe from the vial by turning it anti-clockwise and releasing it from the clear endof the transfer device.7. Inspect the reconstituted Cinryze solution for particulate matter prior to administration; do notuse if particles are observed.8. Attach the venipuncture set to the syringe containing Cinryze solution and inject intravenouslyinto the patient. Administer 500 IU (reconstituted in 5 ml of water for injections) of Cinryze byintravenous injection at a rate of 1 ml per minute over 5 minutes.

Administration process for a dose of 1 000 IU1. Aseptic technique should be used during the administration procedure.2. After reconstitution, the Cinryze solutions are colourless to slightly blue and clear. Do not usethe product if the solutions are turbid or discoloured.3. Using a sterile, disposable 10 ml syringe, draw back the plunger to allow approximately 5 ml ofair into the syringe.4. Attach the syringe onto the top of the clear end of the transfer device by turning it clockwise.5. Invert the vial gently and inject air into the solution and then slowly withdraw the reconstituted

Cinryze solution into the syringe.6. Detach the syringe from the vial by turning it anti-clockwise and releasing it from the clear endof the transfer device.7. Using the same syringe, repeat steps 3 to 6 with a second vial of reconstituted Cinryze to makeone complete 10 ml dose.8. Inspect the reconstituted Cinryze solution for particulate matter prior to administration; do notuse if particles are observed.9. Attach the venipuncture set to the syringe containing Cinryze solution and inject intravenouslyinto the patient. Administer 1 000 IU (reconstituted in 10 ml of water for injections) of Cinryzeby intravenous injection at a rate of 1 ml per minute over 10 minutes.

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

Takeda Manufacturing Austria AG

Industriestrasse 671221 Vienna

AustriamedinfoEMEA@takeda.com

EU/1/11/688/001

Date of first authorisation: 15 June 2011

Date of latest renewal: 26 May 2016

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

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