Cinryze

1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



2 

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



3 

• 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. 
 



4 

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.  



5 

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 very common adverse reactions observed following Cinryze infusion in clinical studies were 
headache and nausea. 
 
Tabulated list of adverse reactions 
Adverse reaction frequencies were estimated from 2 pivotal placebo-controlled and 2 open-label 
studies in 251 unique subjects. Only frequencies based on reporting rates from clinical trials are used 
to assign frequency category. 
 
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). 
 



6 

Table 1. Adverse reactions reported in clinical studies and in postmarketing reports 
 
System Organ Class Frequency Adverse reaction 

Immune system disorders Common Hypersensitivity 

Metabolism and nutrition disorders Uncommon Hyperglycaemia 

Nervous system disorders 
Very common headache 

Common Dizziness 

Vascular disorders Uncommon Venous thrombosis, phlebitis, venous burning, hot flush 
Respiratory, thoracic and mediastinal 
disorders Uncommon Cough 

Gastrointestinal disorders 

Very common Nausea 

Common vomiting 

Uncommon Diarrhoea, abdominal pain 

Skin and subcutaneous tissue disorders 
Common Rash, erythema, pruritus 

Uncommon Contact dermatitis,  
Musculoskeletal and connective tissue 
disorders Uncommon Joint swelling, arthralgia, myalgia 

General disorders and administration 
site conditions 

Common Injection site rash/erythema, infusion site pain, pyrexia 

Uncommon Chest discomfort,  

 
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 the national reporting system 
listed in Appendix V. 
  



7 

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.   



8 

 
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 



9 

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.  
 



10 

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). 
 



11 

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 (15ºC - 25ºC).  
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.  



12 

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. 



13 

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  

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



14 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE 
SUBSTANCE(S) AND MANUFACTURER RESPONSIBLE 
FOR BATCH RELEASE 

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION 

 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 

 



15 

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND 
MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 
Name and address of the manufacturer of the biological active substance 
 
Sanquin Plasma Products B.V.   
Plesmanlaan 125 
NL-1066 CX Amsterdam 
The Netherlands 
 
Name and address of the manufacturer responsible for batch release 
 
Takeda Manufacturing Austria AG 
Industriestrasse 67 
1221 Vienna 
Austria 
 
Baxter AG 
Industriestrasse 67 
1221 Vienna 
Austria 
 
Shire International Licensing B.V. 
Strawinskylaan 481 
1077 XX Amsterdam 
The Netherlands 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
 
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product 
Characteristics, section 4.2). 
 
• Official batch release 
 
In accordance with Article 114 of Directive 2001/83/EC, the official batch release will be undertaken 
by a state laboratory or a laboratory designated for that purpose. 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic Safety Update Reports 
 
The requirements for submission of periodic safety update reports for this medicinal product are 
set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of 
Directive 2001/83/EC and any subsequent updates published on the European medicines web-
portal.  
 
 



16 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT   

 
• Risk Management Plan (RMP) 
 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in 
the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed 
subsequent updates of the RMP. 
 
An updated RMP should be submitted: 
• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 

 
 
• Additional risk minimisation measures 
 

 Prior to launch of the product in each Member State, the Marketing Authorisation Holder shall 
agree the content and format of the educational material with the national competent authority. 

 
The Marketing Authorisation Holder (MAH) should ensure that all healthcare professionals who 
are expected to prescribe Cinryze are provided with an Educational pack. 
 
The educational pack should contain the following: 
 

 Summary of Product Characteristics and Patient Information Leaflet for Cinryze 
  
 Educational material for healthcare professionals 
  
 Educational materials for non-healthcare professionals 

 
The educational material for healthcare professionals should include information on the 
following key elements: 
 
There are limited data on the use of this medicinal product in home or self-administration.  
 
It is the responsibility of the prescribing physician to determine which patients may be suitable 
for home or self-administration of Cinryze  
 
It is the responsibility of the prescribing physician to provide appropriate training to the non-
healthcare professional who will administer the treatment at home, such as the patient for self- 
administration or a family member. Regular review of the administration by the patient/carer 
needs to be performed to ensure maintenance of optimal practice. 
 
The training to be provided should address the following elements 
Precaution for storage  
Doses and Indications of treatment 
Preparation of one dose of Cinryze (500 IU) by reconstituting one vial 
Preparation of one dose of Cinryze (1000 IU) by reconstituting two vials 
Method of reconstitution of each vial  
Technique of intravenous injection 
Method and rate of administration of one dose of Cinryze (500 IU) 
Method and rate of administration of one dose of Cinryze (1000 IU) 
Instruction to seek emergency treatment by health care professionals in case of failure to gain 
venous access or in case of lack of efficacy 



17 

Instruction in handling possible adverse reactions 
Information on the need to keep a diary to document each treatment received at home and to 
bring it at each visit. The information collected should include: 
Date and time of treatment 
Batch number and dose received 
Indication for treatment (acute attack or prophylaxis) 
Response to treatment 
Any adverse reactions  
 
It is the responsibility of the prescribing physician to verify that all the necessary skills have 
been acquired by the non-healthcare professional and that Cinryze may be safely and effectively 
administered at home. 
 
The existence of a post marketing registry in which health care professionals are encouraged to 
enter patients 
 
The educational material for non-healthcare professionals should include information on the 
following key elements: 
 
There are limited data on the use of this medicinal product in home or self-administration.  
 
For some patients the prescribing physician may decide that Cinryze may be administered at 
home by a non-healthcare professional such as a family member or by self-administration. 
 
Necessary skills have to be acquired by  non-healthcare professionals before Cinryze may be 
safely and effectively administered at home.  
 
Their prescribing physician will provide training on the following elements: 
Precaution for storage  
Doses and indications of treatment 
Preparation of one dose of Cinryze (500 IU) by reconstituting one vial 
Preparation of one dose of Cinryze (1000 IU) by reconstituting two vials 
Method of reconstitution of each vial  
Technique of intravenous injection 
Method and rate of administration of one dose of Cinryze (500 IU) 
Method and rate of administration of one dose of Cinryze (1000 IU) 
Instruction to seek emergency treatment by health care professionals in case of failure to gain 
venous access or in case of lack of efficacy 
Instruction in handling possible adverse reactions 
Information on the need to keep a diary to document each treatment received at home and to 
bring it at each visit. The information collected should include: 
Date and time of treatment 
Batch number and dose received 
Indication for treatment (acute attack or prophylaxis) 
Response to treatment 
Any adverse reactions  
A leaflet providing detailed information on the key elements of the training that should be kept 
at home for further reference.  

 



18 

• Obligation to conduct post-authorisation measures 
 
The MAH shall complete, within the stated timeframe, the below measures: 
 
Description Due date 
A post-marketing registry should be set-up with the objective to gain additional 
information on the safety and the use of Cinryze in the EU.  Further information to 
be collected includes data on drug exposure, adverse drug reactions, frequency of 
attacks, long-term safety data, use in pregnant patients with outcome of 
pregnancies, as well as use in the paediatric population. Particular attention should 
be given to the monitoring of cases of severe and laryngeal attacks as well as cases 
where treatment started later than 4 hours after onset of attack; details about the 
administered dose, timing of dosing, safety and efficacy outcome should be 
reported. Data collected in this registry should be reported to the CHMP at the time 
of PSUR submissions. 

PSUR Cycle 

 
 



19 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



20 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



21 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Cinryze 500 IU powder and solvent for solution for injection 
C1 inhibitor (human) 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE 
 
After reconstitution, one vial contains 500 IU of C1 inhibitor (human) per 5 ml corresponding to a 
concentration of 100 IU/ml. Two vials of reconstituted Cinryze are combined for a single dose.  
 
 
3. LIST OF EXCIPIENTS 
 
Powder vial: sodium chloride, sucrose, sodium citrate, L-valine, L-alanine, L-threonine 
Solvent vial: water for injections 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder and solvent for solution for injection. 
 
2 powder vials,  
2 solvent vials  
2 filter transfer devices 
2 disposable 10 ml syringes 
2 venipuncture sets 
2 protective mats 
 
 
5. METHOD AND ROUTE OF ADMINISTRATION 
 
Intravenous use. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP  
 



22 

9. SPECIAL STORAGE CONDITIONS 
 
Store below 25ºC. Do not freeze. Store in original package in order to protect from light. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Shire Services BVBA 
Rue Montoyer 47  
B - 1000 Brussels  
Belgium 
 
 
12. MARKETING AUTHORISATION NUMBER 
 
EU/1/11/688/001    
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Cinryze 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
 



23 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
CINRYZE VIAL LABEL  
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE OF ADMINISTRATION 
 
Cinryze 500 IU powder for solution for injection 
C1 inhibitor (human) 
IV Use 
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
500 IU 
 
 
6. OTHER 
 



24 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
SOLVENT VIAL LABEL  
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Solvent for Cinryze  
Water for injections 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
5 ml 
 
 
6. OTHER 
 



25 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



26 

 
PACKAGE LEAFLET: INFORMATION FOR THE USER  

 
Cinryze 500 IU powder and solvent for solution for injection 

C1 inhibitor (human) 
 

This medicine is subject to additional monitoring. This will allow quick identification of new 
safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects. 

 
Read all of this leaflet carefully before you start taking this medicine. 
 
• Keep this leaflet. You may need to read it again. 
• If you have any further questions, ask your doctor or pharmacist. 
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
• If you get any side effects talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaftlet. See section 4. 
 
What is in this leaflet:  
 
1. What Cinryze is and what it is used for 
2. What you need to know before you take Cinryze 
3. How to take Cinryze 
4. Possible side effects 
5. How to store Cinryze 
6. Contents of the pack and other information 
 
 
1. What Cinryze is and what it is used for 
 
Cinryze contains the human protein called “C1 inhibitor” as the active substance.   
 
C1 inhibitor is a naturally occurring protein that is normally present in the blood. If you have a low 
amount of C1 inhibitor in your blood or your C1 inhibitor is not working properly, this can lead to 
swelling attacks (called angioedema). Symptoms may include stomach pains and swelling of the:  
• hands and feet 
• face, eyelids, lips or tongue 
• voice-box (larynx), which may make breathing difficult 
• genitals 
 
In adults and children, Cinryze can raise the amount of C1 inhibitor in the blood and either prevent 
(prior to undergoing medical or dental procedures) these swelling attacks from occurring or stop 
swelling attacks once they have begun. 
In adults, adolescents and children (aged 6 years and above), Cinryze can raise the amount of C1 
inhibitor in the blood and routinely prevent swelling attacks from occurring. 
 
 
2. What you need to know before you take Cinryze 
 
Do not take Cinryze 
• If you are allergic to C1 inhibitor or any of the other ingredients of Cinryze (listed in section 6). 

It is important to tell your doctor if you think you have ever had an allergic reaction to any of 
the ingredients in Cinryze. 

 



27 

Warnings and precautions 
• Before you start treatment with Cinryze, it is important that you tell your doctor if you have, or 

have had, problems with your blood clotting (thrombotic events). You will be carefully 
monitored if this is the case. 

• If you begin to suffer from rashes, tightness of the chest, wheezing, or a fast heart beat once you 
have taken Cinryze, you should tell your doctor immediately (see section 4). 

• When medicines are made from human blood or plasma, certain measures are put in place to 
prevent infections being passed on to patients. These include careful selection of blood and 
plasma donors to make sure those at risk of carrying infections are excluded, and the testing of 
each donation and pools of plasma for signs of virus/infections. Manufacturers of these products 
also include steps in the processing of the blood or plasma that can inactivate or remove viruses. 
Despite these measures, when medicines prepared from human blood or plasma are 
administered, the possibility of passing on infection cannot be totally excluded. This also 
applies to any unknown or emerging viruses or other types of infections.  
 
The measures taken are considered effective for enveloped viruses such as human 
immunodeficiency virus (HIV), hepatitis B and hepatitis C viruses, and for the non-enveloped 
hepatitis A and parvovirus B19 viruses. 
 
Your doctor may recommend that you consider having vaccinations against hepatitis A and B if 
you regularly or repeatedly receive C1 inhibitor products that have been taken from human 
plasma. 
 
It is strongly recommended that every time you receive a dose of Cinryze the name and batch 
number of the product are recorded by your nurse or doctor in order to maintain a record for the 
batches used.  

 
Children 
 
Cinryze is not for use in children below 6 years of age for routine prevention of angioedema attacks. 
 
Other medicines and Cinryze 
 
Tell your doctor if you are taking, have recently taken or might take any other medicines.   
 
Pregnancy and breast-feeding 
 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor for advice before taking Cinryze. There is limited information on the safety of Cinryze use 
during pregnancy and breast-feeding. Your doctor will discuss with you the risks and benefits of 
taking this medicine. 
 
Driving and using machines 
 
Cinryze has minor influence on the ability to drive and use machines.  
 
Cinryze contains sodium 
 
Each vial of Cinryze contains approximately 11.5 mg of sodium. This should be taken into account by 
people on a controlled sodium diet. 
 
 
3. How to take Cinryze 
 
Your treatment will be initiated and managed under supervision of a doctor experienced in the care of 
patients with hereditary angioedema (HAE). 
 



28 

A doctor or nurse may prepare and inject Cinryze for you. If your doctor decides you can self-
administer, your doctor or nurse will train you or a family member to prepare and inject Cinryze. Your 
doctor will regularly review the preparation and administration process with you or a family member 
or carer. 
 
The recommended dose of Cinryze for adults, adolescents, children, the elderly, or patients suffering 
from kidney or liver problems is as follows: 
 
Adults and adolescents (12 years and above) 
 
Treatment of swelling attacks 
• A dose of 1000 IU (two vials) of Cinryze should be injected at the first sign of a swelling attack.   
• A second injection of 1000 IU may be given if your symptoms do not improve after 60 minutes. 
• If you are experiencing a severe attack, particularly a swelling of the voice-box (larynx), or if 

initiation of treatment is delayed, the second 1000 IU dose may be given earlier than 60 minutes 
after the first dose, depending on your clinical response. 

• Cinryze should be injected intravenously (into the vein). 
 
Routine prevention of swelling attacks 
• A dose of 1000 IU (two vials) of Cinryze should be injected every 3 or 4 days for routine 

prevention of swelling attacks.  
• The dosing interval may be adjusted by your doctor depending upon your response to Cinryze. 
• Cinryze should be injected intravenously (into the vein). 
 
Prevention of swelling attacks prior to surgery 
• A dose of 1000 IU (two vials) of Cinryze should be injected up to 24 hours before a medical, 

dental, or surgical procedure. 
• Cinryze should be injected intravenously (into the vein). 
 
Children 

Treatment of angioedema attacks Pre-procedure prevention 
of angioedema attacks 

Routine prevention of 
angioedema attacks 

2 to 11 years, >25 kg: 
A dose of 1000 IU (two vials) of 
Cinryze should be injected at the first 
sign of a swelling attack. 
 
A second injection of 1000 IU may be 
given if your symptoms do not improve 
after 60 minutes. 
 
2 to 11 years, 10-25 kg:  
A dose of 500 IU (one vial) of Cinryze 
should be injected at the first sign of a 
swelling attack. 
 
A second injection of 500 IU may be 
given if your symptoms do not improve 
after 60 minutes. 
 

2 to 11 years, >25 kg: 
A dose of 1000 IU (two 
vials) of Cinryze should 
be injected up to 24 hours 
before a medical, dental, 
or surgical procedure. 
 
 
 
2 to 11 years, 10-25 kg:  
A dose of 500 IU (one 
vial) of Cinryze should be 
injected up to 24 hours 
before a medical, dental, 
or surgical procedure. 
 

6 to 11 years: 
A dose of 500 IU (one vial) 
of Cinryze should be injected 
every 3 or 4 days for routine 
prevention of swelling 
attacks. 
 
The dosing interval may be 
adjusted by your doctor 
depending upon your 
response to Cinryze. 
 

 
Reconstitution and method of administration 
 
Cinryze is usually injected into a vein (intravenously) by your doctor or nurse. You or your carer 
might also administer Cinryze as an injection, but only after receiving adequate training. If you are 
injecting Cinryze yourself, always use it exactly as your doctor has instructed you. Check with your 



29 

doctor if you are not sure. If your doctor decides that you may be suitable for such home-treatment, 
he/she will give you detailed instructions. You will be required to keep a diary in order to document 
each treatment received at home and to bring it to each of your visits to the doctor. Regular review of 
your/your carer’s injection technique will be performed to ensure continued appropriate handling.  
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, Cinryze can cause side effects, although not everybody gets them.  
 
This can include allergic-type reactions. 
 
Tell your doctor immediately if you experience any of the following symptoms after taking this 
medicine. Although they are rare, the symptoms can be severe.  
 
Sudden wheeziness, difficulty in breathing, swelling of eyelids, face or lips, rash or itching (especially 
affecting the whole body).  
 
Very common side effects (may affect more than 1 in 10 people): headache, nausea.  
 
Common side effects (may affect up to 1 in 10 people): hypersensitivity, dizziness, vomiting, rash, 
itching or redness, injection site rash or pain, fever.  
 
Uncommon side effects (may affect up to 1 in 100 people): high blood sugar, blood clot, painful veins, 
hot flush, cough, stomach pain, diarrhoea, skin flaking, joint swelling and pain, muscle pain, and chest 
discomfort.  
 
Side effects in children and adolescents are expected to be similar to those in adults.  
 
Reporting of side effects 
 
If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not 
listed in this leaflet. You can also report side effects directly via the national reporting system listed in 
Appendix V. By reporting side effects you can help provide more information on the safety of this 
medicine. 
 
 
5. How to store Cinryze 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use Cinryze after the expiry date which is stated on the carton or vials after “EXP”.  
Store below 25°C. Do not freeze. Store in the original package in order to protect from light. 
 
Once reconstituted, Cinryze solution should be used immediately.  
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help to protect the environment. 
 
 



30 

6. Contents of the pack and other information 
 
What Cinryze contains 
 
The active substance is C1 inhibitor produced from the plasma of human donors. Each powder vial 
contains 500 IU of C1 inhibitor. After reconstitution, one vial contains 500 IU of C1 inhibitor (human) 
per 5 ml, corresponding to a concentration of 100 IU/ml. Two vials of reconstituted Cinryze contain 
1000 IU of C1 inhibitor (human) per 10 ml, corresponding to a concentration of 100 IU/ml.  
 
The total protein content of the reconstituted solution is 15 ± 5 mg/ml. 
 
One International Unit (IU) is equivalent to the amount of C1 inhibitor present in 1 ml of normal 
human plasma.  
 
The other ingredients (excipients) are:  
Powder vial: sodium chloride, sucrose, sodium citrate, L-valine, L-alanine and L-threonine. See 
section 2). 
Solvent vial: water for injections. 
 
What Cinryze looks like and contents of the pack 
 
Cinryze is a white powder contained in a vial. 
 
After it has been dissolved in the water for injections the solution is clear and colourless to slightly 
blue. 
 
Each pack of Cinryze contains: 
2 vials of Cinryze 500 IU powder for solution for injection 
2 vials of water for injections (5 ml each) 
2 filter transfer devices 
2 disposable 10 ml syringes 
2 venipuncture sets 
2 protective mats 
 
Only use a silicone-free syringe (provided in the pack) for administration of the product. 
 
Marketing Authorisation Holder and Manufacturer: 
 
Marketing Authorisation Holder 
Shire Services BVBA 
Rue Montoyer 47 
B - 1000 Brussels Belgium 
medinfoeuceemea@shire.com 
 
Manufacturer 
Takeda Manufacturing Austria AG 
Industriestrasse 67 
1221 Vienna 
Austria 
 
Baxter AG 
Industriestrasse 67 
1221 Vienna 
Austria 
 



31 

Shire International Licensing B.V. 
Strawinskylaan 481 
1077 XX Amsterdam 
The Netherlands 
 
This leaflet was last revised in . 
 
Other sources of information 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu/. There are also links to other websites about rare diseases and treatments. 



32 

The following information is intended for healthcare professionals only: 
 
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.  
 
Only use a silicone-free syringe (provided in the pack) for administration of the product. 
 
Preparation and handling 
Cinryze is intended for intravenous administration (into the vein) after reconstitution with water for 
injections. 
Cinryze vial is for single use only.   
 
Reconstitution 
For a dose of 500 IU: One powder vial, 1 solvent vial, 1 filter transfer device, 1 disposable 10 ml 
syringe, 1 venipuncture set and 1 protective mat are needed. Store the remaining vial and 
administration equipments for the next dose. 
 
For a dose of 1000 IU: Two powder vials, 2 solvent vials, 2 filter transfer devices, 1 disposable 10 ml 
syringe, 1 venipuncture set and 1 protective mat are needed. 
 
Each product vial should be reconstituted with 5 ml water for injections. 
One vial of reconstituted Cinryze corresponds to a dose of 500 IU. Therefore only reconstitute one vial 
of Cinryze for one 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 (15ºC - 25ºC).   
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.  
 
 
 
 
 
 
 
 
 
 
 



33 

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. 
 
 
 
 
 
 
 
 
 
 



34 

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.  

 
 
 
 
 
 
 
 
 
 



35 

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 vein) 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.   

 
 
 
 
 
 
 
 
 



36 

 
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 vein) into the patient. Administer 1000 IU (reconstituted in 10 ml of water for 
injections) of Cinryze by intravenous injection (into the vein) 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. 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET