The following clinically significant adverse reactions are described elsewhere in the labeling: Risk of Low Blood Pressure [see Warnings and Precautions (5.1) ] Most common adverse reactions (>10%) are injection site erythema, injection site swelling, rash, vomiting, injection site urticaria, arthralgia, decreased blood pressure, and gastroenteritis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact BioMarin Pharmaceutical Inc. at 1-866-906-6100, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical 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. Pediatric Patients 5 Years of Age and Older VOXZOGO was studied in a 52-week, randomized, double-blind, placebo-controlled trial in 121 subjects with achondroplasia (Study 1) [see Clinical Studies (14) ] .
The subjects' ages ranged from 5.1 to 14.9 years with a mean of 8.7 years. Sixty four (53%) subjects were male and 57 (47%) were female. Overall, 86 (71%) subjects were White, 23 (19%) were Asian, 5 (4%) were Black or African American, and 7 (6%) were classified as "multiple" race. The demographic and baseline characteristics were balanced between treatment groups. The subjects received either VOXZOGO 15 mcg/kg, or placebo administered subcutaneously once daily.
Table 3 shows adverse reactions that occurred in ≥5% of patients treated with VOXZOGO and at a percentage greater than placebo. Table 3: Adverse Reactions that Occurred in ≥5% of Patients Treated with VOXZOGO and at a Percentage Greater than Placebo in Study 1 Includes adverse reactions occurring more frequently in the vosoritide arm and with a risk difference of ≥5% (i.e., difference of >2 subjects) between treatment arms Adverse Reaction Placebo (N=61) n (%) VOXZOGO (N=60) n (%) Abbreviations: N, total number of subjects in the treatment arm; n, number of subjects with the adverse reaction; %, percent of subjects with the adverse reaction.
Injection site erythema 42 (69%) 45 (75%) Injection site swelling 22 (36%) 37 (62%) Vomiting 12 (20%) 16 (27%) Injection site urticaria 6 (10%) 15 (25%) Arthralgia 4 (7%) 9 (15%) Decreased blood pressure 3 (5%) 8 (13%) Gastroenteritis Includes the preferred terms: gastroenteritis and gastroenteritis, viral 5 (8%) 8 (13%) Diarrhea 2 (3%) 6 (10%) Dizziness Includes the preferred terms: dizziness, presyncope, procedural dizziness, vertigo 2 (3%) 6 (10%) Ear pain 3 (5%) 6 (10%) Influenza 3 (5%) 6 (10%) Fatigue Includes the preferred terms: fatigue, lethargy, malaise 2 (3%) 5 (8%) Seasonal allergy 1 (2%) 4 (7%) Dry skin 0 3 (5%) Laboratory Abnormalities Increase in Alkaline Phosphatase More VOXZOGO-treated patients had an increase in alkaline phosphatase levels during the study compared to placebo (17% vs 7%).
Discussion of Selected Adverse Reactions Decreased blood pressure Eight (13%) of 60 subjects treated with VOXZOGO had a total of 11 events of transient decrease in blood pressure compared to 3 (5%) of 61 subjects on placebo, identified predominantly during periods of frequent monitoring at clinical visits after dosing over a 52-week treatment period. The median time to onset from injection was 31 (18 to 120) minutes with resolution within 31 (5 to 90) minutes in VOXZOGO-treated subjects.
Two out of 60 (3%) VOXZOGO-treated subjects each had one symptomatic episode of decreased blood pressure with vomiting and/or dizziness compared to 0 of 61 (0%) subjects on placebo. Injection site reactions Injection site reactions occurred in 51 (85%) subjects receiving VOXZOGO and 50 (82%) subjects receiving placebo over a 52 week period of treatment. Injection site reactions included the preferred terms injection site erythema, injection site reaction, injection site swelling, injection site urticaria, injection site pain, injection site bruising, injection site pruritus, injection site hemorrhage, injection site discoloration, and injection site induration.
Over a 52 week period, 51 (85%) of 60 subjects receiving VOXZOGO experienced a total of 6983 events of injection site reactions, while 50 (82%) of 61 subjects receiving placebo experienced a total of 1776 events of injections site reactions, representing 120.4 events per person/year exposure and 29.2 per person/year exposure, respectively. One injection site reaction event could have been associated with one or more injection site reaction symptoms (e.g., injection site swelling, injection site erythema, injection site urticaria, etc.).
Two subjects in the VOXZOGO arm discontinued treatment due to adverse reactions of pain and anxiety with injections. Pediatric Patients <5 Years The safety of VOXZOGO in pediatric patients <5 years with achondroplasia was evaluated in a 52-week randomized, double blind, placebo-controlled study (Study 2) . In this study, 64 patients from 4.4 months to <5 years of age were randomized to receive either a daily vosoritide dose with similar exposure to that characterized to be safe and effective in children with ACH aged ≥5 years old, or placebo.
An additional 11 patients received open-label treatment as part of this study. Subjects received 30 mcg/kg while they were <2 years of age. The daily dose for subjects was adjusted to 15 mcg/kg immediately following their 2 year birthday. The most common adverse reactions (>10%) reported in pediatric patients <5 years were injection site reactions (86%) and rash (28%). The overall safety profile of VOXZOGO in pediatric patients <5 years was similar to that seen in older pediatric patients.
