Krystexxa - summary of medicine characteristics

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 PARTICULARS4.1 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).

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 ^mol/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 chlori.de 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 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 ^mol/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 uratelowering 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 weigh t*

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).

Retreatmen t 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.

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 reactio ns^»/

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.

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 premedicated 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 gmo’/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 infusionand 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.

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 PROPERTIES5.1 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 a ction

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.

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-Value2
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

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 2.2" 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 ug/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*|jg/ml (range: 223 – 1040 h*^g/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 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 PARTICULARS6.1 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.

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).

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