6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: Anaphylaxis [see Warnings and Precautions ( 5.1 )] Most common adverse reactions (≥1 patient) are: infusion site extravasation, diarrhea, rash, anaphylaxis, infusion site swelling, peripheral swelling and pruritus. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Ultragenyx at toll-free phone # or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The MEPSEVII clinical program included 23 patients aged 5 months to 25 years who received treatment with MEPSEVII at doses up to 4 mg/kg once every two weeks for up to 164 weeks. Nineteen patients were younger than 18 years of age. Of these 23 patients, 20 patients were evaluable for adverse reactions and 23 patients were evaluable for immunogenicity. Adverse Reactions from the Randomi z ed Start Trial Table 2 summarizes the adverse reactions that occurred in Study 301, a randomized start trial in 12 patients with MPS VII between the ages of 8 and 25 years [see Clinical Studies ( 14 )]. Adverse reactions in Table 2 occurred in one or more patients treated with MEPSEVII at a dosage of 4 mg/kg at a higher patient frequency than placebo. Adverse reaction incidence rates are presented in the table below to account for the different duration of exposure to active treatment vs. placebo. Table 2. Adverse Reactions in Patients with MPS VII in Study 301 Adverse Reaction MEPSEVII N =12 n ( Incidence Rate*) Placebo N= 9 n ( Incidence Rate*) Infusion site extravasation 4 (0.5) 1 (0.4) Diarrhea 3 (0.4) 0 (0.0) Rash 3 (0.4) 2 (0.7) Anaphylaxis 2 (0.2) 0 (0.0) Infusion site swelling 1 (0.1) 0 (0.0) Peripheral swelling 1 (0.1) 0 (0.0) Pruritus 1 (0.1) 0 (0.0) n = number of reactions *Adverse reaction incidence rates calculated per 8.3 patient years for exposure to MEPSEVII, and 2.7 years of exposure for placebo Febrile Convulsion One patient receiving a dose of 4 mg/kg experienced a febrile convulsion during MEPSEVII treatment at week 66. The infusion was stopped, the patient received anticonvulsants, antipyretics and antibiotics, and the adverse reaction resolved. The patient subsequently was re-challenged without recurrence and continued on treatment. 6.2 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to vestronidase alfa-vjbk with the incidence of antibodies to other products may be misleading. Immunogenicity data were available from 23 patients. Eighteen out of 23 patients (78%) developed anti-vestronidase alfa-vjbk antibodies (ADA). Ten of the 18 (55.6%) ADA-positive patients developed neutralizing antibodies (NAb) on at least one occasion. There is no correlation between ADA titer and NAb development. Six treatment naïve patients had pre-existing ADA titers at baseline. ADAs were detected in five of these six patients post-treatment. The post-treatment ADA titers were the same as or below the baseline ADA titer values in two patients, but one of these two patients was positive for NAb. ADA titer values after treatment increased 64-fold in two patients and 364-fold in the third patient. The presence of ADA titer does not appear to affect reduction in the pharmacodynamic marker, urinary glycosaminoglycans (uGAGs), as assessed in clinical trials.