This information is intended for use by health professionals

  This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1. Name of the medicinal product

Cinryze 500 IU powder and solvent for solution for injection

2. Qualitative and quantitative composition

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

After reconstitution, one vial contains 500 IU of C1 inhibitor (human) per 5 ml corresponding to a concentration of 100 IU/ml. One IU is equivalent to the amount of C1 inhibitor present in 1 ml of normal human plasma.

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

Excipient with known effect:

Each vial of Cinryze contains approximately 11.5 mg of sodium.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Powder and solvent for solution for injection.

White powder.

The solvent is a clear, colourless solution.

4. Clinical particulars
4.1 Therapeutic indications

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 or insufficiently protected by oral prevention treatments, or patients who are inadequately managed with repeated acute treatment.

4.2 Posology and method of administration

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

Posology

Adults

Treatment of angioedema attacks

• 1000 IU of Cinryze at the first sign of the onset of an angioedema attack.

• A second dose of 1000 IU may be administered if the patient has not responded adequately after 60 minutes.

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

Routine prevention of angioedema attacks

• 1000 IU of Cinryze every 3 or 4 days is the recommended starting dose for routine prevention against angioedema attacks; the dosing interval may need to be adjusted according to individual response. The continued need for regular prophylaxis with Cinryze should be reviewed on a regular basis.

Pre-procedure prevention of angioedema attacks

• 1000 IU of Cinryze within 24 hours before a medical, dental, or surgical procedure.

Paediatric population

Adolescents

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

Children

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

Treatment of angioedema attacks

Pre-procedure prevention of angioedema attacks

Routine prevention of angioedema attacks

2 to 11 years, >25 kg:

1000 IU of Cinryze at the first sign of the onset of an acute attack.

A second dose of 1000 IU may be administered if the patient has not responded adequately after 60 minutes.

2 to 11 years, 10-25 kg:

500 IU of Cinryze at the first sign of the onset of an acute attack.

A second dose of 500 IU may be administered if the patient has not responded adequately after 60 minutes.

2 to 11 years, >25 kg:

1000 IU of Cinryze within 24 hours before a medical, dental, or surgical procedure.

2 to 11 years, 10-25 kg:

500 IU of Cinryze within 24 hours before a medical, dental, or surgical procedure.

6 to 11 years:

500 IU of Cinryze every 3 or 4 days is the recommended starting dose for routine prevention against angioedema attacks. The dosing interval and dose may need to be adjusted according to individual response. The continued need for regular prophylaxis with Cinryze should be reviewed on a regular basis.

Elderly patients

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

Patients with renal or hepatic impairment

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

Method of administration

For intravenous use.

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

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

4.3 Contraindications

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

4.4 Special warnings and precautions for use

Thrombotic events

Thrombotic events have been reported in neonatal and infant subjects undergoing cardiac bypass procedures while receiving off-label high doses of another C1 inhibitor product (up to 500 Units(*)/kg) to prevent capillary leak syndrome. Based upon an animal study there is a potential thrombogenic threshold at doses greater than 200 Units(*)/kg. Patients with known risk factors for thrombotic events (including indwelling catheters) should be monitored closely.

(*) [Historically assigned potency values were relative to an in-house reference standard whereby 1 Unit (U) is equal to the mean quantity of C1 inhibitor present in 1 ml of normal human plasma.] An international reference standard (IU) has now been implemented where IU is also defined as the amount of C1 inhibitor present in 1 ml of normal human plasma.

Transmissible agents

Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation/removal of viruses. Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infective agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens.

The measures taken are considered effective for enveloped viruses such as HIV, HBV and HCV, and for the non-enveloped viruses HAV and parvovirus B19.

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

It is strongly recommended that every time Cinryze is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the product.

Hypersensitivity

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

Home-treatment and self-administration

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

Paediatric population

Thrombotic events have been reported in neonatal and infant subjects undergoing cardiac bypass procedures while receiving off-label high doses of another C1 inhibitor product (up to 500 Units(*)/kg) to prevent capillary leak syndrome.

Sodium

Each vial of Cinryze contains approximately 11.5 mg of sodium. To be taken into consideration by patients on a controlled sodium diet.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

4.6 Fertility, pregnancy and lactation

Pregnancy

Data on a limited number of exposed pregnancies indicate no adverse effects of C1 inhibitor on pregnancy or on the health of the foetus/newborn child. To date, no other relevant epidemiological data are available. No maternal or embryofoetal effects of treatment were observed in reproductive studies in rats at dose levels up to 28-times the recommended human dose (1000 IU) based on an average adult body weight of 70 kg. The potential risk for humans is unknown.

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

Breast-feeding

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

Fertility

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

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of the safety profile

The only common adverse reaction observed following Cinryze infusion in clinical studies was rash; descriptions of rash characteristics were non-specific, but were typically described as involving the upper extremities, chest, abdomen, or injection site. None of the rashes were serious, and none led to discontinuation of medicinal product. Hypersensitivity reactions may occur (see section 4.4).

Tabulated list of adverse reactions

Adverse reaction frequency was estimated primarily based on summation of unique Cinryze-related adverse events reported across 8 completed clinical studies in HAE subjects. This includes data from two placebo-controlled studies, three open-label studies, three compassionate-use subjects and postmarketing reports. There were a total of 385 subject exposures involving over 14,500 infusions of Cinryze in these studies.

Adverse reactions to treatment with Cinryze are classified by MedDRA System Organ Class and absolute frequency in Table 1. Within each frequency grouping, adverse reactions are presented in order 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 postmarketing reports

System Organ Class

Frequency:

Adverse reaction

Immune system disorders

Not known:

Hypersensitivity

Metabolism and nutrition disorders

Uncommon:

Hyperglycaemia

Nervous system disorders

Uncommon:

Dizziness, headache

Vascular disorders

Uncommon:

Venous thrombosis, phlebitis, venous burning, hot flush

Respiratory, thoracic and mediastinal disorders

Uncommon:

Cough

Gastrointestinal disorders

Uncommon:

Nausea, vomiting, diarrhoea, abdominal pain

Skin and subcutaneous tissue disorders

Common:

Uncommon:

Rash

Contact dermatitis, erythema, pruritus

Musculoskeletal and connective tissue disorders

Uncommon:

Joint swelling, arthralgia, myalgia

General disorders and administration site conditions

Uncommon:

Injection site rash/erythema, infusion site pain, chest discomfort, pyrexia

Description of selected adverse reactions

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

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

Paediatric population

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

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. Healthcare professionals are asked to report any suspected adverse reactions via,

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail:

[email protected]

4.9 Overdose

No case of overdose has been reported.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Drugs used in hereditary angioedema, C1 inhibitor, plasma derived, ATC code: B06AC01.

Mechanism of action

C1 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 inhibitor is a single chain glycoprotein found in plasma which, in its mature state, consists of 478 amino acids with an apparent molecular weight of 105 kD.

C1 inhibitor inhibits the complement system by binding C1r and C1s, two of the active enzyme subunits of the first component of the complement system (C1) in the classical pathway, as well as to mannose-binding lectin-associated serine proteases in the lectin pathway. The primary substrate of the activated C1 enzyme is C4; uninhibited C1 results in diminished C4 levels. C1 is the most important inhibitor of contact activation and regulates the contact system and the intrinsic coagulation pathway by binding to and inactivating kallikrein and factor XIIa. Because these pathways are part of enzyme amplification cascades, without C1 inhibitor, spontaneous or trigger-induced activation of these pathways can lead to unopposed activation and swelling.

Pharmacodynamic effects

In clinical studies, the intravenous administration of Cinryze resulted in a significant increase in systemic levels of antigenic and functional C1 inhibitor within 1 hour after administration. Administration of C1 inhibitor increases serum levels of C1 inhibitor activity and temporarily restores the natural regulation of the contact, complement, and fibrinolytic systems thereby controlling the swelling or the propensity to swell.

Low serum C4 levels often correlate with HAE attacks. Treatment with Cinryze resulted in elevation of C4 levels at 12 hours. There was a statistically significant (p=0.0017) difference in the changes in mean 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).

Clinical efficacy and safety

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 paediatric clinical studies (0624-203 and 0624-301) demonstrated the efficacy of Cinryze for the treatment and prevention of angioedema attacks in subjects with HAE.

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 study demonstrated that treatment with Cinryze within 4 hours after the onset of an HAE attack resulted in a greater than 2-fold decrease in the time to beginning of unequivocal relief of the defining symptom of the 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 to complete 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 symptom within 4 hours after dosing was 60% for Cinryze and 42% for placebo (p=0.062). Among 15 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 attacks achieved unequivocal relief of the defining symptom. For 95% of attacks, clinical relief was observed and/or subjects were discharged to home within 4 hours. For subjects with >1 attack, the proportion of attacks responding within 4 hours after Cinryze dosing and the time to response was comparable regardless of the number of attacks treated. Among 84 separate laryngeal HAE attacks, none required intubation 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 study demonstrated that prophylaxis with Cinryze resulted in a greater than 2-fold reduction in the number of 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 compared to 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 swelling during prophylactic Cinryze therapy was reduced compared to placebo (mean 10.1 days vs. 29.6 days or a 66% reduction, p<0.0001). In addition, fewer open-label Cinryze infusions were required for treatment 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 periods ranging from 8 days to approximately 32 months (median 8 months). Prior to enrollment, subjects reported a median monthly HAE attack rate of 3.0 (range: 0.08-28.0); during therapy with prophylactic Cinryze, this rate was 0.21 (range: 0-4.56), and 86% of subjects experienced an average of ≤1 attack per month. For subjects receiving Cinryze prophylaxis for at least 1 year, the monthly 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 surgical procedures across the clinical programme (40 procedures in children and 51 procedures in adults). For 98% of procedures, no HAE attacks were reported within the 72 hours after the Cinryze dose.

Paediatric population

Age-Group 6-11 years:

Treatment:

Study LEVP 2006-1: Twenty-two paediatric subjects were treated for 121 acute HAE attacks. The proportion 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) 1000 Units(*), and 3 subjects (>25 kg) 1500 Units(*). All 9 (100%) subjects achieved unequivocal beginning of relief of the defining symptom within 4 hours following initiation of treatment with Cinryze. Median interval was 0.5 hours (range: 0.25-2.5 hours): 1.25, 0.25, and 0.5 hours in the 500 Units(*), 1000 Units(*), and 1500 Units(*) Cinryze groups, respectively. Median interval to complete resolution of the HAE attack for the 9 subjects was 13.6 hours (range: 1.6-102.3 hours).

Prevention:

Study LEVP 2006-4: Prior to enrollment, 23 children (age range: 3 to 17 years) reported a median monthly HAE attack rate of 3.0 (range: 0.5-28.0). During the study while receiving Cinryze prophylaxis (1000 Units(*) every 3 to 7 days; with the exception of a 3 year old child, receiving 500 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 per month; these results were comparable to those observed in adults.

Study 0624-301: Six pediatric subjects (6 to 11 years of age ) were enrolled and randomized to twice weekly dosing for 12 weeks in 2 treatment sequences (500/1000 Units(*) or 1000/500 Units(*) Cinryze. Both doses resulted in similar reduction of attack-frequency and showed clinical benefit regarding severity, duration, and requirement for acute treatment of attacks.

Age-group <6years:

For the 3 subjects less than 6 years, administration of Cinryze (500 Units(*) or 1000 Units(*)) was associated with increases in C1 INH levels and clinical efficacy in acute treatment and prevention of attacks. Overall administration of Cinryze was well tolerated.

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

5.2 Pharmacokinetic properties

A randomised, parallel group, open-label pharmacokinetic study of Cinryze was performed in subjects with non-symptomatic HAE. The subjects received either a single intravenous dose of 1000 Units(*) or a 1000 Units(*) dose followed by a second dose of 1000 Units(*) 60 minutes later. The mean pharmacokinetic parameters for functional C1 inhibitor derived from baseline-corrected concentration data are presented in Table 2.

Table 2. Mean Pharmacokinetic Parameters for Functional C1 Inhibitor Following Administration of Cinryze

Parameters

Single Dose

(1000 Units*)

Double Dose

(1000 Units dose followed by a second 1000 Units dose 60 minutes later)

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) (U*hr/ml)

24.5 ± 19.1 (n=12)

39.1 ± 20.0 (n=12)

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 concentration of functional C1 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 single to double dose, although the increase was not dose-proportional. The mean elimination half-life of functional C1 inhibitor after administration of Cinryze was 56 hours for a single dose and 62 hours for the double dose.

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

Paediatric population

Functional C1 inhibitor activity was measured in children in the two open label studies (see section 5.1). Mean increases from baseline in functional C1 inhibitor activity measured 1 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 INH antigen and functional activity from 9 patients were obtained following a single IV dose of 500 Units(*), 1000 Units(*), or 1500 Units(*) Cinryze based on body weight (see section 5.1). Increases in C1 INH antigen levels and functional activity above the baseline values at 1 hour and 24 hours post-dose were demonstrated.

In Study 0624-301, plasma C1 INH antigen and functional activity were measured from 6 patients pre-dose and 1h following IV administration of two dose levels of Cinryze (500 Units(*) and 1000 Units(*)) every 3 or 4 days for 12 weeks. Both Cinryze doses resulted in relevant plasma levels of C1 INH antigen and functional activity.

5.3 Preclinical safety data

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

6. Pharmaceutical particulars
6.1 List of excipients

Powder:

Sodium chloride

Sucrose

Sodium citrate

L-valine

L-alanine

L-threonine

Solvent:

Water for injections

6.2 Incompatibilities

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

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

6.3 Shelf life

2 years.

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

6.4 Special precautions for storage

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.

6.5 Nature and contents of container

500 IU of C1 inhibitor in a colourless glass vial (Type I), sealed 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.

6.6 Special precautions for disposal and other handling

Each kit contains material for either one 1000 IU dose or two 500 IU doses.

Reconstitution and administration of Cinryze

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

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

Preparation and handling

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

Cinryze vial is for single use only.

Reconstitution

One powder vial, 1 solvent vial, 1 filter transfer device, 1 disposable 10 ml syringe, 1 venipuncture set and 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 venipuncture set and 1 protective mat is needed to prepare one dose of 1000 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 1000 IU. Therefore two vials are combined for one dose of 1000 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°C - 25°C).

4. Release the powder vial label by tearing down the perforated strip indicated by the inverted triangle.

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 the device from the package.

8. Note: the transfer device must be attached to the solvent vial before being attached to the powder vial, so that the vacuum in the powder vial is not lost. Place the solvent vial on a flat surface and insert the blue end of the transfer device into the solvent vial, pushing down until the 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 the exposed end of the transfer device.

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

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

powder vial. Make sure all the powder is completely dissolved.

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

One vial of reconstituted Cinryze contains 500 IU of C1 inhibitor in 5 ml, resulting in a 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 (1000 IU/10 ml). Therefore, repeat instructions 1 to 12 above using an additional package containing a transfer device to reconstitute the second of two powder vials. Do not reuse the transfer device. Once the two vials are reconstituted proceed to administration process for a dose of 1000 IU

Administration process for a dose of 500 IU

1. Aseptic technique should be used during the administration procedure.

2. After reconstitution, the Cinryze solutions are colourless to slightly blue and clear. Do not use the 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 of air 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 end of the transfer device.

7. Inspect the reconstituted Cinryze solution for particulate matter prior to administration; do not use if particles are observed.

8. Attach the venipuncture set to the syringe containing Cinryze solution and inject intravenously into the patient. Administer 500 IU (reconstituted in 5 ml of water for injections) of Cinryze by intravenous injection at a rate of 1 ml per minute over 5 minutes.

Administration process for a dose of 1000 IU

1. Aseptic technique should be used during the administration procedure.

2. After reconstitution, the Cinryze solutions are colourless to slightly blue and clear. Do not use the 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 of air 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 end of the transfer device.

7. Using the same syringe, repeat steps 3 to 6 with a second vial of reconstituted Cinryze to make one complete 10 ml dose.

8. Inspect the reconstituted Cinryze solution for particulate matter prior to administration; do not use if particles are observed.

9. Attach the venipuncture set to the syringe containing Cinryze solution and inject intravenously into the patient. Administer 1000 IU (reconstituted in 10 ml of water for injections) of Cinryze by 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 local requirements.

7. Marketing authorisation holder

Shire Services BVBA

Rue Montoyer 47

B - 1000 Brussels

Belgium

8. Marketing authorisation number(s)

EU/1/11/688/001

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 15 June 2011

Date of latest renewal: 26 May 2016

10. Date of revision of the text

09 2017

Detailed information on this product is available on the website of the European Medicines Agency http://www.ema.europa.eu