Krystexxa

1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 

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1. NAME OF THE MEDICINAL PRODUCT 
 
KRYSTEXXA 8 mg concentrate for solution for infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each vial contains 8 mg of pegloticase (8 mg/ml concentrate). The strength indicates the quantity of 
the uricase moiety of pegloticase without consideration of the PEGylation. 
 
The active substance pegloticase is a covalent conjugate of uricase produced by a genetically modified 
strain of Escherichia coli and monomethoxypoly (ethylene glycol). 
 
The potency of this product should not be compared to the one of another pegylated or non-pegylated 
protein of the same therapeutic class. 
 
For the full list of excipients see section 6.1 
 
 
3. PHARMACEUTICAL FORM 
 
Concentrate for solution for infusion. 
 
Clear to slightly opalescent, colourless solution at pH 7.3±0.3. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
KRYSTEXXA is indicated for the treatment of severe debilitating chronic tophaceous gout in adult 
patients who may also have erosive joint involvement and who have failed to normalize serum uric 
acid with xanthine oxidase inhibitors at the maximum medically appropriate dose or for whom these 
medicines are contraindicated (see section 4.4). 
 
The decision to treat with KRYSTEXXA should be based on an on-going assessment of the benefits 
and risks for the individual patient (see section 4.4). 
 
4.2 Posology and method of administration 
 
Treatment should be initiated and supervised by specialist physicians experienced in the diagnosis and 
treatment of severe refractory chronic gout. 
 
The medicinal product should be administered in a healthcare setting and by healthcare professionals 
prepared to manage anaphylaxis and infusion reactions. Close monitoring is required during the 
infusion and for at least 2 hours after the end of the infusion. Availability of resuscitation equipment 
must be ensured. Delayed-type hypersensitivity reactions have also been reported. 
 
Posology 
 
The recommended dose is 8 mg pegloticase given as an intravenous infusion every two weeks. 
 
Prior to infusion, patients should receive pre-medication to minimize the risk of infusion-related 
reactions, e.g. antihistamine the evening before, and again approximately 30 minutes before the 
infusion, as well as paracetamol and a corticosteroid immediately before each infusion (see 
section 4.4). 
 

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Monitoring of serum uric acid level is required prior to each infusion. KRYSTEXXA should not be 
administered if two consecutive levels above 6 mg/dl (360 µmol/L) have been measured (see 
section 4.4). 
 
Before starting the treatment and especially before monitoring the serum uric acid levels, patients 
should discontinue oral urate-lowering medication and not institute therapy with oral urate-lowering 
medication while taking KRYSTEXXA (see section 4.4). 
 
The optimal treatment duration has not been established (see section 4.4). The duration of treatment 
should be based upon maintenance of response (serum uric acid levels < 6 mg/dl) and clinical 
judgment. 
 
Patients with renal impairment 
Based on similar efficacy and safety profiles of pegloticase in patients with creatinine clearance 
below and above 50 ml/min, no dose adjustment is required for patients with renal impairment (see 
section 5.2).  
 
Elderly patients 
No dose adjustment is needed for patients 65 years of age and older (see section 5.2). 
 
Paediatric population 
The safety and efficacy of KRYSTEXXA in children and adolescents aged below 18 years has not 
been established. No data are available.   
 
Method of administration 
KRYSTEXXA, once diluted with 250 ml of sodium chloride solution, 4.5 mg/ml (0.45%) or 9 mg/ml 
(0.9%), is administered as an intravenous infusion over no less than 2 hours, at a flow rate of 
approximately 2 ml/minute.  
 
For instructions on the preparation of the medicinal product before administration, see section 6.6. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
Glucose-6-phosphate dehydrogenase (G6PD) deficiency and other cellular metabolic disorders known 
to cause haemolysis and methemoglobinemia. All patients at higher risk for G6PD deficiency (e.g., 
patients of African or Mediterranean ancestry) should be screened for G6PD deficiency before starting 
KRYSTEXXA.  
 
4.4 Special warnings and precautions for use 
 
The benefit/risk balance should be assessed for each individual patient on an on-going basis 
considering the effect on tophus resolution as well as the risk of infusion reactions, gout flares, and 
potentially increased cardiac risk. The long-term risk of prophylactic medications to prevent infusion 
reactions, such as glucocorticoids, should also be taken into consideration.  
 
The data for long-term treatment from controlled clinical studies are limited. This should be 
considered when the decision is made for a therapy longer than 6 months. 
 
Infusion-related reactions / Anaphylaxis 
KRYSTEXXA can induce severe allergic responses, including anaphylactic shock with cardiac arrest. 
Special attention is recommended for patients with pre-existing cardiopulmonary disease. 
 
Patients should be pre-treated with antihistamines, corticosteroids, and paracetamol, and closely 
monitored for the onset of adverse reactions suggesting severe hypersensitivity reactions including 
anaphylaxis for at least 1 hour after the end of the infusion (see section 4.8). If an infusion reaction 

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occurs during the administration, the infusion may be slowed, or stopped and restarted at a slower rate, 
at the discretion of the physician. 
 
Most infusion-related reactions have been observed after loss of therapeutic response due to the 
development of anti-pegloticase antibodies, i.e. when serum uric acid values were above 6 mg/dl 
(360 µmol/L). Therefore, monitoring of serum uric acid level is required prior to each infusion. 
KRYSTEXXA should be discontinued if 2 consecutive levels above 6 mg/dl have been measured.  
 
Since concomitant use of oral urate-lowering therapy may potentially mask the rise of serum uric acid 
associated with the loss of response, patients taking concomitant oral urate-lowering therapy may be at 
increased risk of infusion reactions and/or anaphylaxis. It is therefore recommended to discontinue 
oral urate-lowering medications before starting treatment and not institute therapy with oral urate-
lowering agents while taking KRYSTEXXA.  
 
Acute gouty attacks (gout flare) 
An increase in gout flares is frequently observed upon treatment initiation, probably as a result of 
mobilization of urate from tissue deposits. To reduce the likelihood of gout flares after initiation of 
KRYSTEXXA prophylaxis with colchicine or a non-steroidal anti-inflammatory drug (NSAID) is 
recommended. It is recommended to start this treatment 1 week before initiation of KRYSTEXXA and 
continue for at least 6 months, unless medically contraindicated or not tolerated. 
 
KRYSTEXXA does not need to be interrupted because of a gout flare, which should be managed 
concurrently as appropriate for the individual patient. Continuous treatment with pegloticase decreases 
frequency and intensity of gout flares. 
 
Congestive heart failure 
KRYSTEXXA has not been formally studied in patients with congestive heart failure, but a small 
number of patients with pre-existing cardiovascular conditions who were treated with pegloticase in 
the clinical trials had exacerbations of their congestive heart failure. Caution should be exercised in 
patients who have congestive heart failure and patients should be monitored closely following 
infusion. 
 
Haemolysis and/or Methemoglobinemia 
If haemolysis and/or methemoglobinemia occur in patients receiving KRYSTEXXA, treatment should 
be immediately and permanently discontinued and appropriate measures initiated. 
 
Patients over 100 kg body weight 
Lower response rates were observed in patients over 100 kg BW; however, confounding factors in a 
small sample size make it unclear if in patients over 100 kg BW the dose was optimal to achieve an 
effect. Also, high titres of anti-pegloticase antibodies and infusion-related reactions showed a tendency 
to occur in a greater proportion of patients in this weight group (see section 4.8). 
 
Retreatment with KRYSTEXXA 
Very limited data are available about retreatment after interruption of therapy for more than 4 weeks. 
Because of the immunogenicity of KRYSTEXXA, patients receiving retreatment may be at increased 
risk of infusion-related reactions, including anaphylaxis. It is therefore recommended that patients 
given repeat infusions of KRYSTEXXA after a treatment interruption be monitored carefully. 
 
Sodium intake  
KRYSTEXXA contains 4.2 mg sodium (less than 1 mmol) per dose (essentially sodium free).  
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No interaction studies have been performed. 
 

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As anti-pegloticase antibodies can bind to the PEG moiety of KRYSTEXXA, there may be potential 
for binding to other PEGylated products. It is unknown whether the development of anti-PEG 
antibodies may reduce the efficacy of other PEGylated medicinal products.  
 
4.6 Fertility, Pregnancy and Lactation 
 
Pregnancy 
There are no data from the use in pregnant women. The embryofetal development study in rats does 
not indicate direct or indirect harmful effects with respect to reproductive toxicity. The results of the 
on-going reproductive toxicity studies are not available (see section 5.3). KRYSTEXXA is not 
recommended during pregnancy. 
 
Breast-feeding 
It is unknown whether pegloticase or its metabolites are excreted in human milk. A risk to the 
newborns/infants cannot be excluded. Therefore, KRYSTEXXA should not be used during 
breast-feeding unless the clear benefit to the mother can overcome the unknown risk to the 
newborn/infant.  
 
Fertility 
Effect on male and female fertility has not been studied. 
 
4.7 Effects on ability to drive and use machines 
 
KRYSTEXXA has no or negligible influence on the ability to drive and use machines. If patients 
experience treatment-related symptoms affecting their ability to concentrate and react (i.e. headache or 
dizziness), it is recommended that they do not drive or use machines until the effect subsides. 
 
4.8 Undesirable effects 
 
Summary of safety profile 
In controlled clinical trials, the most commonly reported serious adverse reactions were anaphylaxis, 
which occurred at a frequency of 6.5% (8/123) in patients treated with 8 mg every 2 weeks; infusion 
reactions, which occurred at a frequency of 26% and gout flares, which were more common during the 
first 3 months of treatment.  
 
Tabulated list of adverse reactions 
The following convention has been used for classification of the adverse reactions reported in the 
Phase 3 clinical trials (see Table 1 below): very common (≥1/10), common (≥1/100 to <1/10), 
uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known 
(cannot be estimated from the available data). Within each frequency grouping and system organ class, 
adverse reactions are presented in order of decreasing seriousness. 
 

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Table 1.  Adverse Reactions  
System Organ Class Adverse Reaction  
Metabolism and nutrition disorders Common: Hyperglycaemia 

Uncommon: Hyperkalaemia  
Cardiac disorders Uncommon: Exacerbation of congestive heart failure 
Gastrointestinal disorders Very common: Nausea  

Common:  Vomiting 
Skin and subcutaneous disorders Very common: Dermatitis, urticaria, pruritus, skin 

irritation, dry skin 
Uncommon: Cellulitis 

Musculoskeletal and connective tissue 
disorders 

Very common: Gout flare 
Common: Joint swelling 

Blood and lymphatic disorders Not known: Haemolysis 

General disorders and administration 
site conditions 

Very common: Infusion related reaction 
Common: Anaphylaxis, influenza like illness 

 
Description of selected adverse reactions 
 
Infusion-related reactions 
Infusion-related reactions can occur after initiation of any infusion, in spite of patients being pre-
medicated with oral antihistamine, intravenous corticosteroid and/or paracetamol, and generally during 
or within 1 hour after the infusion is completed. The first infusion reaction usually occurs after the 2nd 
to 4th infusion. 
 
The most common signs and symptoms of local infusion reactions are: erythema, pruritus, and rash. 
The most common signs and symptoms of systemic infusion reactions are: urticaria, dyspnoea, 
flushing, hyperhidrosis, chest discomfort or pain, chills, and hypertension. 
 
Anaphylaxis (characterized by stridor, wheezing, peri-oral/lingual oedema, or hemodynamic 
instability, with or without rash or urticaria) occurred in 14 (5.1%) of 273 total patients treated with 
KRYSTEXXA in clinical studies. One patient treated with KRYSTEXXA 8 mg every 4 weeks 
experienced a delayed type hypersensitivity reaction. 
 
In clinical trials, 91% of patients who experienced an infusion-related reaction had a serum uric acid 
level above 6 mg/dl (360 μmol/L) due to the development of anti-pegloticase antibodies. 
 
Infusion-related reactions showed a tendency to occur in a greater proportion of patients with over 
100 kg bodyweight. They were reported in 54% of the patients in the 70 to ≤100 kg weight group, 
70% of the patients in the >100 to ≤120 kg weight group, and 75% of patients in the >120 kg weight 
group, respectively. 
 
Many infusion-related reactions resolved with slowing, or stopping the infusion, before restarting the 
infusion at a slower rate. Others resolved with supportive treatment with i.v. fluids, additional 
glucocorticoids or antihistamines, or following discontinuation of the infusion and with epinephrine 
for anaphylactic reactions.  
 
In the post-marketing setting, severe anaphylactic reactions have been reported, including loss of 
consciousness, circulatory collapse, and cardiac arrest, which required transfer to hospital emergency 
department. 
 
Gout flares 
The frequency of gout flares may increase after initiation of treatment with KRYSTEXXA, despite 
gout prophylaxis with colchicine or NSAIDs, but the frequency and severity of gout flares diminishes 
after 3 months of KRYSTEXXA therapy. 

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In clinical trials, the percentage of patients that had flares in the first 3 months was 75% in patients 
treated with KRYSTEXXA 8 mg every 2 weeks compared with 54% in placebo-treated patients. This 
compared with flare rates of 41%and 67% in the same groups in the subsequent 3 months, and gout 
flares were infrequent in patients that received pegloticase 8 mg every 2 weeks for over one year.  
 
Immunogenicity 
In clinical trials, anti-pegloticase antibodies (IgM and IgG) developed in 89% of patients treated with 
KRYSTEXXA 8 mg every 2 weeks and 15% in the placebo group. Anti-PEG antibodies also 
developed in 41% of patients treated with KRYSTEXXA 8 mg every 2 weeks.  
 
High anti-pegloticase antibody titres were associated with a failure to maintain normalisation of uric 
acid (<6 mg/dl).  
 
There was also a higher incidence of infusion reactions in patients with high anti-pegloticase antibody 
titres: 46% (18 of 39) in the KRYSTEXXA every 2 weeks group compared to 9% (4 of 46) in patients 
with low or no antibody titres. 
 
4.9 Overdose 
 
No case of overdose with KRYSTEXXA has been reported during clinical development. The 
maximum dose that has been administered as a single intravenous dose during clinical studies was 
12 mg. A post-marketing report documented administration of the contents of 2 vials (16 mg) without 
any adverse reaction related to KRYSTEXXA administration. 
 
It is recommended that patients suspected of receiving an overdose be monitored, and general 
supportive measures be initiated as no specific antidote has been identified. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Anti-gout preparations, other anti-gout preparations, ATC code: 
M04AX02 
 
Pegloticase is a uricase enzyme conjugated with mPEG at an average degree of substitution of 
40.8 moles of mPEG/mole of protein (10.2 moles of mPEG/monomeric sub-unit of the mature 
homotetrameric uricase protein). The average molecular mass of pegloticase is approximately 545 kDa 
of which the protein moiety constitutes approximately 137 kDa. 
 
Mechanism of action 
Pegloticase catalyses the conversion of uric acid into the inert highly water-soluble metabolite 
allantoin, with hydrogen peroxide and carbon dioxide as oxidative by-products. Allantoin is eliminated 
by renal excretion, thereby lowering serum uric acid. This induces a concentration gradient between 
serum uric acid and tissue/joints deposits of monosodium urate resulting in the migration of urate from 
tissues/joints, which makes it accessible to conversion to allantoin. 
 
Pharmacodynamic effects 
In clinical trials, the mean plasma uric acid (PUA) levels fell to 0.7 mg/dl approximately 24 hours 
following the first dose of pegloticase in patients treated with KRYSTEXXA 8 mg every 2 weeks 
compared with a mean PUA of 8.2 mg/dl in the placebo-treated patients. 
 
Plasma uric acid decreased with increasing pegloticase dose or concentration. Sustained decrease in 
plasma uric acid below the solubility concentration of 6 mg/dl was observed for more than 12 days 
with single doses of 8 mg and 12 mg. 
 

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Clinical efficacy and safety 
The efficacy and safety of KRYSTEXXA was assessed in two replicate Phase III pivotal trials (GOUT 
1 and GOUT 2) that were conducted in 212 adult patients with chronic gout refractory to allopurinol. 
 
Patients were randomised in a 2:2:1 ratio to receive 8 mg every 2 weeks or every 4 weeks or placebo 
for 6 months. The mean PUA at baseline was 9.8 mg/dl. Seventy-one percent (71%) of patients had 
baseline tophi. The average number of gout flares per patient was 10 during the 18 months prior to 
study entry. 
 
The primary endpoint in both trials was the proportion of responder patients that achieved plasma uric 
acid (PUA) less than 0.36 mmol/L (6 mg/dl) for at least 80% of the time during Month 3 and Month 6. 
 
As shown in Table 2, a greater proportion of patients treated with KRYSTEXXA 8 mg every 2 weeks 
were responders as compared to patients receiving placebo. Responders maintained PUA values 
< 6 mg/dl throughout the 6-month treatment period. Although the 4-week regimen also demonstrated 
efficacy for the primary endpoint, this regimen was associated with increased frequency of infusion 
reactions. 
 
Table 2.  Plasma Uric Acid < 6 mg/dl for at Least 80% of the Time During Months 3 and 6 

Treatment Group N 
Number (%) of 

Subjects Who Met 
Response Criteria 

95% Confidence 
Interval1 p-Value

2 

GOUT3 1     
   Pegloticase 8 mg every 2 weeks  43 20 (47%) [32%, 61%] <0.001 
   Pegloticase 8 mg every 4 weeks  41 8 (20%) [7%, 32%] 0.044 
   Placebo 20 0 (0%)   
GOUT3 2      
   Pegloticase 8 mg every 2 weeks  42 16 (38%) [23%, 53%] <0.001 
   Pegloticase 8 mg every 4 weeks  43 21 (49%) [34%, 64%] <0.001 
   Placebo 23 0 (0%)   
1 95% confidence interval for differences in responder rate between pegloticase group vs. placebo 
2 P-value using Fisher’s exact test to compare pegloticase group vs. placebo 
3GOUT = Gout Outcomes and Urate-lowering Therapy 
 
The effect of treatment on tophi was assessed using standardized digital photography and image 
analysis by a Central Reader blinded to treatment assignment. As shown in Table 3 at Month 6, the 
percentage of patients who achieved complete tophus response (defined as 100% resolution of at least 
one target tophus, without the appearance of any new tophi or any progression of existing tophi) was 
29.0% in patients treated with 8 mg pegloticase every 2 weeks compared to 6.9% in placebo patients 
excluding patients with missing data, who were considered as a failure. 
 
Table 3.  Overall Complete Tophus Resolution (Pooled Analysis of GOUT 1 and GOUT 2) 

Assessment Time 
point 

8 mg Pegloticase Every 
2 Weeks 
(N = 62) 

Placebo 
(N = 29) 

 

N1 Number of 
Patients with 

CR (%)2 

N1 Number of 
Patients 
with CR 

(%)2 

p-Value3 

Week 13    46 10 (16.1%) 25 0 (0.0%) p≤0.05 
Week 19   44 16 (25.8%) 26 2 (6.9%)  p≤0.05 
Week 25   40 18 (29.0%) 25  2 (6.9%)  p≤0.05 
1 Number of patients with available data 
2 Patients with missing data were considered as a failure 
3 p values based on Fisher’s exact test to compare pegloticase versus placebo 
 

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The HAQ-PGA scores were 42.4 at baseline vs. 27.1 at Week 25 in patients treated with pegloticase 
8 mg every 2 weeks compared to 51.6 vs. 53.4 in the placebo group (p≤0.001). 
 
The HAQ-DI scores were 1.1 at baseline vs. 0.84 at Week 25 in patients treated with pegloticase 8 mg 
every 2 weeks compared to 1.2 vs. 1.3 in the placebo group (p≤0.01). The Pain scores using a visual 
analogue scale were 44.2 at baseline vs. 28.4 at Week 25 in patients treated with pegloticase 8 mg 
every 2 weeks compared to 53.9 vs. 57.2 in the placebo group (p≤0.001). 
 
Among the other secondary endpoints, reduction from baseline in the number of tender and swollen 
joints were observed in patients treated with KRYSTEXXA every 2 weeks while there was little 
change in patients on placebo. 
 
Paediatric population 
The European Medicines Agency has deferred the obligation to submit the results of studies with 
KRYSTEXXA in one or more subset of the paediatric population in the treatment and/or prevention of 
hyperuricaemia related to Tumour Lysis Syndrome (see section 4.2 for information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
KRYSTEXXA was administered by intravenous infusion with a Tmax of 2.25 h (range: 1.92 – 4.25 h 
for initial dose). There was potential for some accumulation with the KRYSTEXXA 8 mg every two 
weeks dosing regimen due to the long half-life of pegloticase (214 h; range: 123 - 444 h for terminal 
half-life). The mean Cmax calculated on the last infusion was 2.17 µg/ml (range: 1.25 - 4.77). The mean 
area under the KRYSTEXXA plasma concentration versus time curve at steady-state (AUC0-t) was 
445 h*µg/ml (range: 223 – 1040 h*µg/ml). From the nonclinical studies, the elimination of pegloticase 
is via renal/urinary excretion. For the PEG moiety, urinary excretion is likely to be the major route of 
elimination. 
 
The population PK analyses showed that age, sex and weight did not influence the pharmacokinetics 
of pegloticase. Anti-pegloticase antibodies were associated with an increase in CL and Vc as 
determined by compartmental analysis. Clearance was 0.0145 L/h with a range of 0.00904 – 0.0229 
for no increase in anti-pegloticase antibodies and 0.0193 L/h with a range of 0.00675 – 0.0340 for an 
increase in anti-pegloticase antibodies. The volume of distribution was 4.45 L with a range of 2.62 – 
5.89 for no increase in anti-pegloticase antibodies and 5.77 L with a range of 2.77 – 10.6 for an 
increase in anti-pegloticase antibodies. 
 
The Phase 1 pharmacokinetics showed proportionality within the dose interval (0.5 – 8 mg) as 
reflected in Cmax values. However, due to variability in the AUC values, AUC proportionality was not 
seen which might be a reflection of antibody clearance for some of the subjects. 
 
The PK/PD analysis showed that higher doses were associated with lower uric acid levels and a more 
rapid decrease in these levels than lower doses. Antibodies to pegloticase associated with clearance of 
pegloticase resulted in a small stimulation in the elimination of urate. Those subjects that did not have 
anti- pegloticase antibodies that cleared pegloticase  had a significant effect on the stimulation in the 
elimination of urate. Neither body weight nor baseline creatinine clearance had a significant effect on 
the PD response. 
 
Special populations 
No formal studies were conducted to examine the effects of renal insufficiency on pegloticase 
pharmacokinetics. A total of 32% (27 of 85) of patients treated with KRYSTEXXA 8 mg every 
2 weeks had a creatinine clearance of ≤62.5 ml/min. 
 
No formal studies were conducted to examine the effects of hepatic impairment. 
 
In the clinical studies, 34% (29 of 85) of patients treated with KRYSTEXXA 8 mg every 2 weeks 
were 65 years of age and older and 12% (10 of 85) were 75 years of age and older. No overall 
differences in safety or efficacy were observed between older and younger patients, but greater 

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sensitivity of some older individuals cannot be ruled out. No dose adjustment is needed for patients 
65 years of age and older. 
 
The pharmacokinetics of KRYSTEXXA has not been studied in children and adolescents. 
 
5.3 Preclinical safety data 
 
In repeated dose toxicity studies with KRYSTEXXA in rats and dogs, the occurrence of 
pegloticase-containing vacuoles was observed in different tissues. The degree of vacuolization and the 
number of tissues affected appeared to be dependent both on the applied pegloticase dose and the 
duration of exposure. The potential clinical relevance of these findings is currently unknown; however 
no adverse effects were associated with the presence of vacuoles. 
 
Non-clinical studies to evaluate the carcinogenic and mutagenic potential have not been performed. 
 
In the pregnant rat study there was no evidence of embryotoxicity or teratogenicity at 46 times the 
clinical exposure (AUC). There were no effects on the fertility of male or female rats.  Prenatal and 
postnatal development study in rats, as well as the embryofetal development study in rabbits are 
ongoing. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Disodium hydrogen phosphate dihydrate  
Sodium dihydrogen phosphate dihydrate 
Sodium chloride 
Water for injections 
 
6.2 Incompatibilities 
 
This medicinal product must not be mixed with other medicinal products except those mentioned in 
section 6.6. 
 
6.3 Shelf life 
 
2 years. 
 
Physical and chemical stability of KRYSTEXXA diluted in 250 ml sodium chloride 4.5 mg/ml 
(0.45%) or 9 mg/ml (0.9%) has been demonstrated for 4 hours at 2°C to 8°C and at room temperature 
(20°C to 25°C), if the solution is prepared as described in section 6.6. From a microbiological point of 
view, the product should be used immediately. If the diluted solution is not used immediately, it can be 
stored refrigerated (2°C to 8°C). The solution should be used within 4 hours of dilution (see 
section 6.6). 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2°C to 8°C). Do not freeze. Do not shake. 
 
Keep the vial in the outer carton in order to protect from light. 
 
For storage conditions after dilution of the medicinal product, see section 6.3. 
 

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6.5 Nature and contents of container 
 
2 ml vial (Type I glass) with a Teflon coated bromobutyl rubber stopper and aluminium seal with 
polypropylene flip-off cap, containing 1 ml concentrate for solution for infusion. 
 
Pack size: 1 vial 
 
6.6 Special precautions for disposal and other handling 
 
Instructions for preparation: 
• KRYSTEXXA vial should be visually inspected for particles and discolouration prior to dilution 

and administration. Only solutions which are clear to slightly opalescent, colourless and free of 
visible particles should be used. 

• Appropriate aseptic technique should be used when preparing the infusion. The vial should not 
be shaken. 

• 1 ml of KRYSTEXXA should be withdrawn from the vial into a sterile syringe. 
• 1 ml of KRYSTEXXA should be injected into a single 250 ml bag of sodium chloride 

4.5 mg/ml (0.45%) or 9 mg/ml (0.9%) solution for injection for infusion. 
• The infusion bag containing the diluted KRYSTEXXA solution should be inverted a number of 

times gently to ensure thorough mixing. The infusion bag containing diluted KRYSTEXXA 
should not be shaken. 

• Before administration, the diluted solution of KRYSTEXXA should be allowed to reach room 
temperature. KRYSTEXXA in a vial or in an intravenous infusion fluid must never be subjected 
to artificial heating (e.g., hot water, microwave). 

 
Any unused medicinal product or waste material must be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Crealta Pharmaceuticals Ireland Limited 
Commercial House, Millbank Business Park, Lower Lucan Road, Lucan, Co. Dublin 
Ireland 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/12/810/001 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 08/01/2013 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 

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ANNEX II 
 

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

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
 AUTHORISATION 

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A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 

MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) of the biological active substance 
 
Bio-Technology General (Israel) Ltd. 
Be'er Tuvia Industrial Park 
Kiryat Malachi 83104 
Israel 
 
Name and address of the manufacturer responsible for batch release 
 
United Drug, plc 
United Drug House 
Magna Business Park 
Magna Drive, Citywest Road 
Dublin 24 
Ireland 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to medical prescription (see Annex I: Summary of Product Characteristics, 
section 4.2). 
 
 
C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING  AUTHORISATION  
 
Pharmacovigilance system 
The MAH must ensure that the system of pharmacovigilance presented in Module 1.8.1. of the 
Marketing Authorisation is in place and functioning before and whilst the medicinal product is on the 
market. 
 
Risk Management Plan (RMP) 
The MAH shall perform the pharmacovigilance activities detailed in the Pharmacovigilance Plan, as 
agreed in the Risk Management Plan presented in Module 1.8.2. of the Marketing Authorisation and 
any subsequent updates of the RMP agreed by the Committee for Medicinal Products for Human Use 
(CHMP). 
 
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the 
updated RMP should be submitted at the same time as the next Periodic Safety Update Report 
(PSUR). 
 
In addition, an updated RMP should be submitted: 
• When new information is received that may impact on the current Safety Specification, 

Pharmacovigilance Plan or risk minimisation activities 
• Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being 

reached 
• At the request of the European Medicines Agency. 
 
PSURs  
The PSUR cycle for the medicinal product should follow the standard requirements. 
 
 
• CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE 

USE OF THE MEDICINAL PRODUCT 

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Not applicable. 
 
 
• OBLIGATION TO CONDUCT POST-AUTHORISATION MEASURES 
 
The MAH shall complete, within the stated timeframe, the following measures: 
 
Description Due date 
M0402: EU Pegloticase post-marketing Observational Study 
The applicant should conduct a long-term EU observational study to end 
December 2018 on safety of pegloticase use in adult hyperuricemic patients with 
severe debilitating chronic tophaceous gout and efficacy and safety data in re-
exposed patients. The applicant should submit yearly interim reports. 

Study protocol 
within 2 months 
after Commission 
Decision 

 

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15 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 

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16 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
KRYSTEXXA 8 mg concentrate for solution for infusion 
pegloticase 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each vial contains 8 mg of pegloticase (8 mg/ml concentrate) 
 
 
3. LIST OF EXCIPIENTS 
 
Disodium hydrogen phosphate dihydrate, sodium dihydrogen phosphate dihydrate, sodium chloride, 
water for injections 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Concentrate for solution for infusion 
1 vial 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Intravenous use 
Read the package leaflet before use. 
Do not shake. 
For single use only 
 
 
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 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. Do not freeze. 
Keep the vial in the outer carton in order to protect from light. 
 

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10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Crealta Pharmaceuticals Ireland Limited 
Commercial House, Millbank Business Park, Lower Lucan Road, Lucan, Co. Dublin 
Ireland 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/12/810/001 
 
 
13. BATCH NUMBER  
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted 
 
 

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MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
KRYSTEXXA 8 mg concentrate for solution for infusion 
pegloticase 
Intravenous use  
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER  
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
8 mg / 1 ml  
 
 
6. OTHER 
 
 

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B. PACKAGE LEAFLET 

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Package Leaflet: Information for the user 
 

KRYSTEXXA 8 mg concentrate for solution for infusion 
pegloticase 

 
 

Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor, pharmacist or nurse. 
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. 
 
What is in this leaflet 
1. What KRYSTEXXA is and what it is used for 
2. What you need to know before you receive KRYSTEXXA 
3. How to use KRYSTEXXA 
4. Possible side effects 
5. How to store KRYSTEXXA 
6. Contents of the pack and other information 
 
 
1. What KRYSTEXXA is and what it is used for 
 
KRYSTEXXA contains the active substance pegloticase. Pegloticase belongs to the class anti-gout 
medicines. 
 
Pegloticase is used to treat severe long-term gout in adult patients who also have one or more painful 
deposits of uric acid crystals under the skin that cause difficulty in carrying out daily activities and 
who do not respond or cannot take other anti-gout medicines.  
 
How KRYSTEXXA works 
People with gout have too much uric acid in their body. Uric acid deposits as crystals in joints, 
kidneys, and other organs which may cause profound pain, redness and swelling (inflammation). 
KRYSTEXXA contains an enzyme called uricase that transforms the uric acid into a substance called 
allantoin, which can be removed easily in the urine.  
 
 
2. What you need to know before you receive KRYSTEXXA 
 
Do not use KRYSTEXXA 
• If you are allergic to pegloticase, or other uricases or any of the other ingredients of this 

medicine (listed in section 6). 
• If you have a rare blood problem called glucose 6-phosphate dehydrogenase (G6PD) deficiency 

or favism. Your doctor may test you for G6PD before you start KRYSTEXXA. 
 
Warnings and precautions 
Talk to your doctor or nurse before using KRYSTEXXA: 
 
- if you are currently taking other medicines to lower your uric acid level  
- if you have been told you have heart failure  
- if you have ever been told you have an enzyme deficiency that causes anaemia  
- if you weigh over 100 kg 
- if you have been treated with KRYSTEXXA before 
 

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Monitoring during treatment 
Your doctor will test your blood to measure uric acid levels before each dose to make sure that you 
should continue receiving KRYSTEXXA. 
 
Children and adolescents 
KRYSTEXXA has not been studied in children or adolescents under 18 years of age. Therefore, this 
medicine is not recommended in this age group. 
 
Other medicines and KRYSTEXXA 
Tell your doctor if you are taking, have recently taken or might take any other medicines. It is 
especially important to tell your doctor if you are currently taking other urate-lowering medicines 
(such as allopurinol or Febuxostat) or medicines containing polyethylene glycol (PEG) (such as 
pegylated interferon or Doxorubicin). These medicines may put you at higher risk of infusion reaction.  
 
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 this medicine. Do not use KRYSTEXXA if you are pregnant or 
breast-feeding, since it is not known how it will affect you or your baby. 
 
Driving and using machines 
KRYSTEXXA has little or no effect on your ability to drive. If you do not feel well, experience 
symptoms such as dizziness or headache, or are tired after receiving KRYSTEXXA, you should not 
drive or operate any machines. 
 
KRYSTEXXA contains sodium  
KRYSTEXXA contains 4.2 mg sodium per dose which means it is essentially sodium free. 
 
 
3. How to use KRYSTEXXA 
 
KRYSTEXXA should be given to you by a doctor or nurse experienced in the treatment of severe 
chronic gout in a healthcare centre. 
 
How much KRYSTEXXA is given 
The recommended dose of KRYSTEXXA is 8 mg. This dose is not adjusted for weight, age or kidney 
disease. 
 
Before you start treatment with KRYSTEXXA, your doctor may recommend that you take other 
medicines (such as an antihistamine, paracetamol and a corticosteroid) to help reduce the risk that you 
will get infusion-related reactions due to this treatment. Take these medicines as directed by your 
doctor.  
 
How KRYSTEXXA is administered 
KRYSTEXXA is injected slowly into a vein (i.v. infusion) and your treatment will take about 2 hours 
or sometimes longer. If you have a reaction during the infusion, your doctor may stop or adjust the 
treatment. Your doctor may also ask you to wait after your treatment to be sure that you do not have 
an infusion-related reaction. 
 
You will receive KRYSTEXXA every 2 weeks. 
 
If you stop taking KRYSTEXXA, and then are treated again, you may be at increased risk of infusion 
reactions, including severe acute allergic reactions (anaphylaxis) so your doctor will monitor you 
carefully when you restart treatment. 
 
Your doctor will also test your blood to measure uric acid before your next dose to make sure that you 
should continue receiving KRYSTEXXA. 
 

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If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. The most 
commonly reported serious side effects are: severe acute allergic reactions (common), infusion 
reactions (very common), and gout flares (very common). 
 
KRYSTEXXA will be administered by a doctor or nurse who will monitor you for side effects while 
you receive KRYSTEXXA and for some time afterwards. 
 
Severe allergic reactions (common) include fainting, sudden drop in blood pressure, and cardiac 
arrest. Allergic reactions usually happen within 2 hours of the infusion, but may also happen at a later 
time. 
 
If you suddenly notice: 
• a swelling of the throat, tongue or other part of your body 
• tightness of the throat, hoarse voice or trouble swallowing 
• a shortness of breath, wheezing or breathing problems 
• a rash, itching or hives 
tell your doctor or nurse IMMEDIATELY, since any of these may be signs of a serious allergic 
reaction. 
 
The most common signs and symptoms of local infusion reactions were: redness at the injection site, 
itching, and rash. The most common signs and symptoms of generalised infusion reactions were: 
hives, shortness of breath, redness in the face, sweating, chest discomfort or pain, chills, and high 
blood pressure.  
 
Allergic reactions may be more likely to occur in patients who weigh more than 100 kg. 
 
An increase in gout flares is frequently observed when starting KRYSTEXXA. Your doctor may 
prescribe medicines to reduce the likelihood of gout flares after starting KRYSTEXXA. 
 
KRYSTEXXA does not need to be discontinued because of a gout flare. 
 
Very common side effects (may affect more than 1 in 10 people): hives, skin rash, itchy, dry or 
irritated skin, nausea 
 
Common side effects (may affect up to 1 in 10 people): high blood sugar levels, vomiting, joint 
swelling, flu-like symptoms 
 
Uncommon side effects: (may affect up to 1 in 100 people): worsening of a type of heart disease 
called congestive heart failure, skin infection, elevated potassium levels in the blood 
 
Frequency not known (cannot be estimated from available data): destruction of red blood cells 
 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. 
 
 
5. How to store KRYSTEXXA 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the label and the carton after EXP. 
The expiry date refers to the last day of that month. 

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24 

 
This medicine will be stored in a healthcare facility where it is administered. 
 
Store in a refrigerator (2°C to 8°C). 
Keep the vial in the outer carton in order to protect from light. 
 
From a bacteriological point of view, the product should be used immediately. If the diluted solution is 
not used immediately it can be stored refrigerated (2°C to 8°C). The solution should be used within 4 
hours of dilution. 
 
Do not use this medicine if you notice any particles or discolouration in the diluted solution. 
 
 
6. Contents of the pack and other information 
 
What KRYSTEXXA contains 
• The active substance is pegloticase. Each vial contains 8 mg of pegloticase (8 mg/ml 

concentrate). 
• The other ingredients are disodium hydrogen phosphate dihydrate, sodium dihydrogen 

phosphate dihydrate, sodium chloride and water for injections. 
 
What KRYSTEXXA looks like and contents of the pack 
 
KRYSTEXXA 8 mg concentrate for solution for infusion is supplied in 2 ml glass vials containing 
1 ml concentrate. KRYSTEXXA is a clear to slightly opalescent colourless solution. 
 
Pack size of 1 vial. 
 
Marketing Authorisation Holder 
Crealta Pharmaceuticals Ireland Limited 
Commercial House, Millbank Business Park, Lower Lucan Road, Lucan, Co. Dublin 
Ireland 
 
Manufacturer 
United Drug, plc 
United Drug House 
Magna Business Park 
Magna Drive, Citywest Road 
Dublin 24 
Ireland 
 
 
This leaflet was last revised in {MM/YYYY} 
 
Other sources of information 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.  
------------------------------------------------------------------------------------------------------------------------ 
 
The following information is intended for healthcare professionals only: 
 
KRYSTEXXA must be prepared as follows: 
 
Instructions for preparation of the solution for infusion: 
• KRYSTEXXA vial should be visually inspected for particles and discolouration prior to dilution 

and administration. Only solutions which are clear to slightly opalescent, colourless and free of 
visible particles should be used. 

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• Appropriate aseptic technique should be used when preparing the infusion. The vial should not 
be shaken. 

• 1 ml of KRYSTEXXA should be withdrawn from the vial into a sterile syringe. 
• 1 ml of KRYSTEXXA should be injected into a single 250 ml bag of sodium chloride 

4.5 mg/ml (0.45%) or 9 mg/ml (0.9%) solution for injection or infusion. 
• The infusion bag containing the diluted KRYSTEXXA solution should be inverted a number of 

times gently to ensure thorough mixing. The infusion bag containing diluted KRYSTEXXA 
should not be shaken.  

• Before administration, the diluted solution of KRYSTEXXA should be allowed to reach room 
temperature. KRYSTEXXA in a vial or in an intravenous infusion fluid must never be subjected 
to artificial heating (e.g., hot water, microwave). 

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

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26 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Annex IV 

Scientific conclusions and grounds recommending the variation to the terms of the Marketing 
Authorisation 

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Scientific conclusions 

Taking into account the PRAC Assessment Report on the PSUR for pegloticase, the scientific 
conclusions of CHMP are as follows:  

Scientific conclusions and grounds for variation to the terms of the marketing authorisations  

Reports of infusion related reactions or anaphylaxis coincident with concomitant use of oral urate 
lowering agents were submitted in this Periodic Safety Update Report, where infusion reactions in 28 
cases and 9 cases with anaphylactic reactions were reported. As the development of these adverse 
events may have been prevented in at least some of these cases if the patients would not have been 
treated with concomitant urate lowering substances, an amendment of the summary of product 
characteristics focusing on the importance of stopping treatment with uric acid lowering agents with 
regard to masking the results of serum uric acid values (and therefore increasing the risk for infusion 
reactions and anaphylactic reactions) should be implemented. The revised order of the two 
corresponding paragraphs is to emphasize the correlation between concomitant medication with urate 
lowering products and serum uric acid measurement. In addition, a further amendment regarding the 
extension of the time of observation following the end of infusion from 1 hour to 2 hours as a 
precautionary measure has been included along with a statement that delayed-type hypersensitivity 
reactions have also been reported.  

Therefore, in view of available data regarding anaphylaxis and infusion reactions, the 
Pharmacovigilance Risk Assessment Committee considered that changes to the product information 
were warranted.  

The CHMP agrees with the scientific conclusions made by the PRAC. 

 

Grounds recommending the variation to the terms of the Marketing Authorisation  

On the basis of the scientific conclusions for pegloticase the CHMP is of the opinion that the 
benefit-risk balance of the medicinal product containing pegloticase is favourable subject to the 
proposed changes to the product information 

The CHMP recommends that the terms of the Marketing Authorisation(s) should be varied. 

 

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	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING  AUTHORISATION 
	A. LABELLING
	B. PACKAGE LEAFLET