Adverse reactions : תופעות לוואי

6 ADVERSE REACTIONS
The following serious adverse reactions are discussed in greater detail in other sections of the label: • Anaphylaxis [see Warnings and Precautions (5.1)]
• Infusion Reactions [see Warnings and Precautions (5.2)]
• G6PD Deficiency Associated Hemolysis and Methemoglobinemia [see Warnings and Precautions (5.3)] • Gout Flares [see Warnings and Precautions (5.4)]
• Congestive Heart Failure [see Warnings and Precautions (5.5)]
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. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@moh.gov.il.

6.1 Clinical Trials Experience
The data described below reflect exposure to KRYSTEXXA® in patients with chronic gout refractory to conventional therapy in two replicate randomized, placebo-controlled, double-blind 6-month clinical trials: 85 patients were treated with KRYSTEXXA® 8 mg every 2 weeks; 84 patients were treated with KRYSTEXXA® 8 mg every 4 weeks; and 43 patients were treated with placebo. These patients were between the ages of 23 and 89 years (average 55 years);
173 patients were male and 39 were female; and 143 patients were White/Caucasian, 27 were Black/African American, 24 were Hispanic/Latino and 18 were all other ethnicities. Common co-morbid conditions among the enrolled patients included hypertension (72%), dyslipidemia (49%), chronic kidney disease (28%), diabetes (24%), coronary artery disease (18%), arrhythmia (16%), and cardiac failure/left ventricular dysfunction (12%).

Because clinical studies are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug, and may not predict the rates observed in a broader patient population in clinical practice.

The most commonly reported adverse reactions that occurred in greater than or equal to 5% of patients treated with KRYSTEXXA® 8 mg every 2 weeks are provided in Table 1.

Table 1. Adverse Reactions Occurring in 5% or More of Patients Treated with KRYSTEXXA® Compared to Placebo

Adverse Reaction                KRYSTEXXA                                           Placebo (Preferred Term)                      8 mg every 2 weeks
(N=85)                                         (N=43)
Na (%)                                                N (%)
Gout flare                               65 (77%)                                            35 (81%) Infusion reaction                        22 (26%)                                             2 (5%) Nausea                                   10 (12%)                                             1 (2%) b                  b          9 (11%)                                              2 (5%) Contusion or Ecchymosis
Nasopharyngitis                          6 (7%)                                               1 (2%) Constipation                             5 (6%)                                               2 (5%) Chest Pain                               5 (6%)                                               1 (2%) Anaphylaxis                              4 (5%)                                               0 (0%) Vomiting                                 4 (5%)                                               1 (2%) a
If the same subject in a given group had more than one occurrence in the same preferred term event category, the subject was counted only once.
b
Most did not occur on the day of infusion and could be related to other factors (e.g., concomitant medications relevant to contusion or ecchymosis, insulin dependent diabetes mellitus).
6.2 Immunogenicity
Anti-pegloticase antibodies developed in 92% of patients treated with KRYSTEXXA® every 2 weeks, and 28% for placebo. Anti-PEG antibodies were also detected in 42% of patients treated with KRYSTEXXA.
High anti-pegloticase antibody titer was associated with a failure to maintain pegloticase-induced normalization of uric acid. The impact of anti-PEG antibodies on patients’ responses to other PEG-containing therapeutics is unknown.

There was a higher incidence of infusion reactions in patients with high anti-pegloticase antibody titer: 53% (16 of 30) in the KRYSTEXXA® every 2 weeks group compared to 6% in patients who had undetectable or low antibody titers.

As with all therapeutic proteins, there is a potential for immunogenicity. The observed incidence of antibody positivity in an assay is highly dependent on several factors including assay sensitivity and specificity and assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease.
For these reasons, the comparison of the incidence of antibodies to pegloticase with the incidence of antibodies to other products may be misleading.

6.3 Postmarketing Experience
The following adverse reactions have been identified during postapproval use of KRYSTEXXA®.
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship.

General disorders and administration site conditions: asthenia, malaise, peripheral swelling.