WARNING: ANAPHYLAXIS Anaphylaxis has occurred with MEPSEVII administration, as early as the first dose [see Warnings and Precautions ( 5.1 )] , therefore appropriate medical support should be readily available when MEPSEVII is administered. Closely observe patients during and for 60 minutes after MEPSEVII infusion [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.1 )]. Immediately discontinue the MEPSEVII infusion if the patient experiences anaphylaxis [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.1 )]. WARNING: ANAPHYLAXIS See full prescribing information for complete boxed warning. Anaphylaxis has occurred with MEPSEVII administration, as early as the first dose ( 5.1 ), therefore appropriate medical support should be readily available when MEPSEVII is administered. Closely observe patients during and for 60 minutes after MEPSEVII infusion ( 2.2 , 5.1 ). Immediately discontinue the MEPSEVII infusion if the patient experiences anaphylaxis ( 2.2 , 5.1 ).
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warnings and cautions
5 WARNINGS AND PRECAUTIONS 5.1 Anaphylaxis Anaphylaxis to MEPSEVII was reported in 2 of 20 patients in the clinical program [see Adverse Reactions ( 6.1 )] . These reactions occurred during MEPSEVII infusion and were observed as early as the first dose of MEPSEVII for one patient. Manifestations included respiratory distress, cyanosis, decreased oxygen saturation, and hypotension. The two patients with anaphylaxis to MEPSEVII during the clinical trials had one occurrence each and tolerated subsequent infusions of MEPSEVII, without recurrence. Anaphylaxis can be life-threatening. MEPSEVII should be administered under the supervision of a healthcare professional with the capability to manage anaphylaxis. Patients should be observed for 60 minutes after MEPSEVII administration. If severe systemic reactions occur, including anaphylaxis, immediately discontinue the MEPSEVII infusion and provide appropriate medical treatment. Prior to discharge, inform patients of the signs and symptoms of anaphylaxis and instruct them to seek immediate medical care if symptoms occur. Consider the risks and benefits of re-administering MEPSEVII following anaphylaxis.
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 1-888-756-8657 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 187 weeks. Nineteen patients were younger than 18 years of age. 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 in the studies described below with the incidence of antibodies in other studies to other vestronidase alfa products may be misleading. Immunogenicity data were available from 23 patients who received MEPSEVII for up to 187 weeks of treatment. Eighteen out of 23 (78%) patients developed anti-vestronidase alfa-vjbk antibodies (ADA). Ten of the 18 (55.6%) ADA-positive patients were tested positive for neutralizing antibodies (NAb). 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, 128-fold, and 364-fold, respectively, in the other three patients. The presence of ADA titer did not appear to affect reduction in urinary glycosaminoglycans (uGAGs).