based on the patient's actual body weight (see table 1 ). voxzogo is administered by subcutaneous injection once daily [see dosage and administration (2.4) ] . inject voxzogo at approximately the same time each day, if possible. the volume of voxzogo to be administered (injection volume) is based on the patient's actual body weight and the concentration of reconstituted voxzogo (0.8 mg/ml or 2 mg/ml) (table 1). voxzogo must be reconstituted prior to use [see dosage and administration (2.4) ] . table 1: recommended voxzogo daily dosage and injection volume actual body weight vial strength for reconstitution the concentration of vosoritide in reconstituted 0.4 mg vial and 0.56 mg vial is 0.8 mg/ml. the concentration of vosoritide in reconstituted 1.2 mg vial is 2 mg/ml. dose injection volume 10-11 kg 0.4 mg 0.24 mg 0.3 ml 12-16 kg 0.56 mg 0.28 mg 0.35 ml 17-21 kg 0.56 mg 0.32 mg 0.4 ml 22-32 kg 0.56 mg 0.4 mg 0.5 ml 33-43 kg 1.2 mg 0.5 mg 0.25 ml 44-59 kg 1.2 mg 0.6 mg 0.3 ml 60-89 kg 1.2 mg 0.7 mg 0.35 ml ≥90 kg 1.2 mg 0.8 mg 0.4 ml missed dose if a dose of voxzogo is missed, it can be administered within 12 hours of the scheduled time of administration. beyond 12 hours, skip the missed dose and administer the next daily dose according to the usual dosing schedule. 2.3 growth monitoring monitor and assess patient body weight, growth, and physical development regularly every 3-6 months. adjust the dosage according to the patient's actual body weight [see dosage and administration (2.2) ] . permanently discontinue voxzogo upon confirmation of no further growth potential, indicated by closure of epiphyses. 2.4 preparation and administration reconstitute voxzogo before administration using the provided diluent syringe containing sterile water for injection, usp (see reconstitution instructions below). caregivers may inject voxzogo subcutaneously after proper training by a healthcare professional on the preparation and administration of voxzogo [see instructions for use ]. reconstitution instructions select the correct voxzogo strength and prefilled diluent syringe co-pack based on the patient's actual body weight [see dosage and administration (2.2) ] . remove voxzogo vial and prefilled diluent syringe (sterile water for injection, usp) from the refrigerator and allow the vial and prefilled diluent syringe to reach room temperature before reconstituting voxzogo. attach the diluent needle provided with ancillary supplies to the diluent prefilled syringe. inject the entire diluent prefilled syringe volume into the vial. gently swirl the diluent in the vial until the white powder is completely dissolved. do not shake. parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. once reconstituted voxzogo is a clear, colorless to yellow liquid. the solution should not be used if discolored or cloudy, or if particles are present. the concentration of reconstituted solution is 0.8 mg/ml or 2.0 mg/ml. after reconstitution, voxzogo can be held in the vial at a room temperature 20°c to 25°c (68°f to 77°f) for a maximum of 3 hours. for administration, extract the required dose volume from the vial using the supplied administration syringe [see dosage and administration (2.2) ] . discard any unused portion. do not pool unused portions from the vials. do not administer more than 1 dose from a vial. do not mix with other medications. instructions for subcutaneous administration see the instructions for use document for detailed, illustrated instructions. ensure patients have had adequate food and fluid intake prior to voxzogo administration [see dosage and administration (2.1) ] . slowly withdraw the dosing volume of the reconstituted voxzogo solution from the single-dose vial into a syringe. rotate sites for subcutaneous injections. the recommended injection sites for voxzogo are: the front middle of the thighs, the lower part of the abdomen at least 2 inches (5 centimeters) away from the navel, top of the buttocks or the back of the upper arms. the same injection area should not be used on two consecutive days. do not inject voxzogo into sites that are red, swollen, or tender.

ed 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 2 shows adverse reactions that occurred in ≥5% of patients treated with voxzogo and at a percentage greater than placebo. table 2: 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 (%) abreviations: 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%) 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. 6.2 immunogenicity as with all peptides, 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 or to other products may be misleading. of 131 subjects who were treated with voxzogo 15 mcg/kg/day and evaluable for the presence of anti-drug antibodies (ada) for up to 240 weeks, ada were detected in 35% (46/131). the earliest time to ada development was day 85. all ada-positive subjects tested negative for anti-vosoritide neutralizing antibodies. there was no correlation between the number, duration, or severity of hypersensitivity adverse reactions or injection site reactions and ada positivity or mean ada titer. there was no association between ada positivity or mean ada titer and change from baseline in annual growth velocity (agv) or height z-score at month 12. there was no impact of serum ada detected on the plasma pk measurements of vosoritide.

jor birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. data animal data in an embryofetal developmental toxicity study in rats, vosoritide was administered at 90, 270, 540 mcg/kg once daily by subcutaneous injection during the period of major organogenesis from gestation day (gd) 6 – 17. there were no effects on maternal animals or on embryofetal development at the highest dose administered (14-times the exposure at the mrhd). in an embryofetal developmental toxicity study in rabbits, vosoritide was administered at 45, 135, 240 mcg/kg once daily by subcutaneous injection during the period of major organogenesis (gd 7 – 19). no effects were observed in maternal animals or on embryofetal development at the highest dose administered (200-times the exposure at the mrhd). in a pre- and postnatal toxicity study in rats, vosoritide was administered at 90, 270, and 540 mcg/kg once daily by subcutaneous injection during the period of major organogenesis and continuing to weaning (gd 6 through postpartum day 20). there were no effects on maternal animals, including maintenance of pregnancy, parturition, or care of offspring, and no effects were noted on offspring growth and development or ability to reproduce at the highest dose (14-times the exposure at the mrhd). 8.2 lactation risk summary there is no information regarding the presence of vosoritide in human milk, the effects on the breastfed infant, or the effects on milk production. vosoritide is present in rat milk. when a drug is present in animal milk, it is likely that the drug will be present in human milk. the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for voxzogo and any potential adverse effects on the breastfed child from voxzogo or from the underlying maternal condition. 8.4 pediatric use the safety and effectiveness of voxzogo have been established in pediatric patients aged 5 years and older for the improvement in linear growth in patients with achondroplasia. use of voxzogo for this indication is supported by evidence from adequate and well-controlled studies in pediatric patients aged 5 years and older [see adverse reactions (6.1) , clinical pharmacology (12.3) , and clinical studies (14) ] . safety and effectiveness of voxzogo in pediatric patients with achondroplasia below the age of 5 years have not been established. 8.6 renal impairment the influence of renal impairment on the pharmacokinetics of voxzogo has not been evaluated. no dosage adjustment is needed for patients with egfr ≥ 60 ml/min/1.73 m 2 . voxzogo is not recommended for patients with egfr < 60 ml/min/1.73 m 2 .

nimal data in an embryofetal developmental toxicity study in rats, vosoritide was administered at 90, 270, 540 mcg/kg once daily by subcutaneous injection during the period of major organogenesis from gestation day (gd) 6 – 17. there were no effects on maternal animals or on embryofetal development at the highest dose administered (14-times the exposure at the mrhd). in an embryofetal developmental toxicity study in rabbits, vosoritide was administered at 45, 135, 240 mcg/kg once daily by subcutaneous injection during the period of major organogenesis (gd 7 – 19). no effects were observed in maternal animals or on embryofetal development at the highest dose administered (200-times the exposure at the mrhd). in a pre- and postnatal toxicity study in rats, vosoritide was administered at 90, 270, and 540 mcg/kg once daily by subcutaneous injection during the period of major organogenesis and continuing to weaning (gd 6 through postpartum day 20). there were no effects on maternal animals, including maintenance of pregnancy, parturition, or care of offspring, and no effects were noted on offspring growth and development or ability to reproduce at the highest dose (14-times the exposure at the mrhd).

normalization of the dwarfism phenotype was observed. 12.2 pharmacodynamics npr-b binding activity biomarker and bone metabolism biomarker an increase in urinary cyclic guanosine monophosphate (cgmp) concentrations from pre-dose baseline were observed within the first four hours post-dose, with a maximum level at 2 hours post-dose, after voxzogo administration to pediatric patients with achondroplasia. daily administration of voxzogo also led to the increase from baseline in serum collagen type x marker (cxm), an endochondral ossification biomarker and remains elevated beyond 24 months. in subjects aged 5 - 14 years old at screening, exposure-response analyses showed that vosoritide activity measured by urinary cgmp was near saturation at the dose of 15 mcg/kg once daily, while maximal increase in growth plate activity indicated by cxm was achieved at this dose. cardiac electrophysiology at the maximum approved recommended dose, voxzogo does not prolong the qt interval to any clinically relevant extent. 12.3 pharmacokinetics the area under the concentration-time curve (auc) and peak concentration (c max ) of vosoritide increased greater than proportionally following subcutaneous administration to pediatric subjects with achondroplasia in the dose range of 7.5 to 30.0 mcg/kg. the pharmacokinetics of vosoritide were evaluated in 58 subjects aged 5 to 13 years with achondroplasia who received subcutaneous injections of vosoritide 15 mcg/kg once daily for 52 weeks. the mean (± sd) c max and area under the concentration-time curve from time zero to the last measurable concentration (auc 0-t ) observed across 52 weeks of treatment ranged from 4.71 (± 2.32) to 7.18 (± 9.65) ng/ml, and 161 (± 98.1) to 290 (± 235) ng-min/ml, respectively. no drug accumulation was observed following 15 mcg/kg once daily dosing. the exposure of vosoritide increased with the duration of treatment. the mean auc 0-t at week 52 increased approximately 20% compared to that at day 1. absorption absolute bioavailability for vosoritide following subcutaneous injection was not determined. vosoritide was absorbed with a median t max of 15 minutes after dosing. distribution the mean (± sd) apparent volume of distribution of vosoritide across 52 weeks of subcutaneous administration of voxzogo 15 mcg/kg once daily ranged from 2880 (± 2450) to 3020 (± 1980) ml/kg. elimination the mean (± sd) apparent clearance of vosoritide across 52 weeks of subcutaneous administration of voxzogo 15 mcg/kg once daily ranged from 79.4 (± 53.0) to 104 (± 98.8) ml/min/kg. the mean (± sd) half-life ranged from 21.0 (± 4.7) to 27.9 (± 9.9) minutes. metabolism the metabolism of vosoritide is expected to occur via catabolic pathways with degradation into small peptide fragments and amino acids. special populations no clinically significant differences in the vosoritide pharmacokinetics were observed based on age (0.9 to 16 years), sex or race. the effect of hepatic or renal impairment on the pharmacokinetics of vosoritide is unknown. body weight population pharmacokinetic analyses indicated that body weight is a significant covariate for vosoritide clearance and volume of distribution. the apparent clearance and volume of distribution of vosoritide increased with increasing body weight in patients with achondroplasia (9 to 74.5 kg). drug interaction studies in vitro assessment of drug-drug interactions in vitro studies showed that vosoritide, at therapeutic concentrations, does not inhibit or induce cytochrome p450 enzymes. in vivo assessment of drug-drug interactions no clinical studies evaluating the drug-drug interaction potential of vosoritide have been conducted.

bioavailability for vosoritide following subcutaneous injection was not determined. vosoritide was absorbed with a median t max of 15 minutes after dosing. distribution the mean (± sd) apparent volume of distribution of vosoritide across 52 weeks of subcutaneous administration of voxzogo 15 mcg/kg once daily ranged from 2880 (± 2450) to 3020 (± 1980) ml/kg. elimination the mean (± sd) apparent clearance of vosoritide across 52 weeks of subcutaneous administration of voxzogo 15 mcg/kg once daily ranged from 79.4 (± 53.0) to 104 (± 98.8) ml/min/kg. the mean (± sd) half-life ranged from 21.0 (± 4.7) to 27.9 (± 9.9) minutes. metabolism the metabolism of vosoritide is expected to occur via catabolic pathways with degradation into small peptide fragments and amino acids. special populations no clinically significant differences in the vosoritide pharmacokinetics were observed based on age (0.9 to 16 years), sex or race. the effect of hepatic or renal impairment on the pharmacokinetics of vosoritide is unknown. body weight population pharmacokinetic analyses indicated that body weight is a significant covariate for vosoritide clearance and volume of distribution. the apparent clearance and volume of distribution of vosoritide increased with increasing body weight in patients with achondroplasia (9 to 74.5 kg). drug interaction studies in vitro assessment of drug-drug interactions in vitro studies showed that vosoritide, at therapeutic concentrations, does not inhibit or induce cytochrome p450 enzymes. in vivo assessment of drug-drug interactions no clinical studies evaluating the drug-drug interaction potential of vosoritide have been conducted.

locity (agv) at week 52 compared with placebo. 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 subjects had a mean baseline height standard deviation score (sds) of -5.13. treatment with voxzogo for 52 weeks resulted in a treatment difference in the change from baseline in agv of 1.57 cm/year after 52 weeks of treatment (table 4). table 4: annualized growth velocity (cm/year) at week 52 in subjects 5 years of age and older with achondroplasia - study 1 placebo (n=61 all randomized subjects. two patients in the voxzogo group discontinued from the study before week 52. the values for these 2 patients were imputed assuming baseline growth rate for the period with missing data. ) voxzogo 15 mcg/kg daily (n=60 ) abbreviations: agv, annualized growth velocity; 95% ci, 95% confidence interval; ls, least-square; sd, standard deviation baseline mean (sd) baseline agv was based on standing height at least 6 months prior to enrollment into the study. 4.06 (1.20) 4.26 (1.53) change from baseline ls means were estimated from the ancova (analysis of covariance) model, which included treatment, stratum defined by sex and tanner stage, baseline age, baseline agv and baseline height z-score. -0.17 1.40 difference in change of voxzogo – placebo (95% ci) 1.57 (1.22, 1.93) 2-sided p-value <0.0001 for superiority. the improvement in agv in favor of voxzogo was consistent across all predefined subgroups analyzed including sex, age group, tanner stage, baseline height z-score, and baseline agv. height standard deviation score (sds) the ls mean change from baseline to week 52 in height sds was -0.02 in the placebo group and 0.26 in the voxzogo group. the difference in ls mean change from baseline was 0.28 (95% ci 0.17, 0.39; p<0.0001) in favor of voxzogo. the ls mean change from baseline to week 52 in upper to lower body segment ratio was -0.02 in the placebo group and -0.03 in the voxzogo group. the difference in ls mean change from baseline was -0.01 (95% ci -0.05, 0.02; p=0.5). open-label extension after the 52 week double blind, placebo-controlled, phase 3 study, study 1, 58 subjects initially randomized to voxzogo enrolled into an open-label extension. among the subjects who had 2 years of follow-up since randomization, the improvement in agv was maintained.

voxzogo to the refrigerator once stored at room temperature. after reconstitution, voxzogo can be held in the vial at room temperature 20°c to 25°c (68°f to 77°f) for a maximum of 3 hours [see dosage and administration (2.4) ] . record the starting date of room-temperature storage clearly on the unopened product carton. do not use beyond expiration date on the label. store in the original package to protect from light. handling reconstituted voxzogo must be administered within 3 hours of reconstitution [see dosage and administration (2.4) ] .

cautions (5.1) ] .

provider about all the medicines your child takes, including prescription and over-the-counter medicines, vitamins, and herbal supplements. know the medicines your child takes. keep a list of them to show your child's healthcare provider and pharmacist when your child gets a new medicine. how should i give voxzogo? see the detailed instructions for use that comes with this patient information leaflet for instructions about the right way to store, prepare, and give voxzogo injections at home. voxzogo is given as an injection under the skin (subcutaneous or sc). inject voxzogo 1 time every day, at about the same time each day. if your child's healthcare provider decides a caregiver can give the injections of voxzogo at home, your child's caregiver should receive training on the right way to prepare and inject voxzogo. do not try to inject voxzogo until you have been shown the right way by your child's healthcare provider or nurse. your child's healthcare provider will tell you how often you should give voxzogo. if your child misses a dose of voxzogo, it can be given within 12 hours of the scheduled time of injection. if more than 12 hours have passed, do not give the missed dose. give the next daily dose according to your child's usual schedule. your child should eat a meal and drink about 8 to 10 ounces of fluid within 1 hour before injection. in case you are not sure when to inject voxzogo, call your child's healthcare provider or pharmacist. do not give voxzogo more often than as directed by your child's healthcare provider. your child's dose of voxzogo depends on his or her body weight. your child's healthcare provider will tell you which strength of voxzogo to use and how much to give your child. your child's healthcare provider will monitor your child's growth and instruct you on when your child should stop voxzogo if they determine that your child is no longer able to grow. stop giving voxzogo to your child if instructed by your child's healthcare provider. what are the possible side effects of voxzogo? voxzogo may cause serious side effects, including: risk of low blood pressure. voxzogo may temporarily lower blood pressure in some people. to help reduce the risk of low blood pressure and its symptoms (dizziness, feeling tired, or nausea), your child should eat a meal and drink about 8 to 10 ounces of fluid within 1 hour before receiving voxzogo. the most common side effects of voxzogo include: injection site reactions (redness, itching, swelling, bruising, rash, hives, pain) vomiting joint pain decreased blood pressure stomach ache these are not all the possible side effects of voxzogo. for more information, ask your healthcare provider or pharmacist. call your doctor for medical advice about side effects. you may report side effects to fda at 1-800-fda-1088. how should i store voxzogo? store the voxzogo vial and prefilled diluent syringe in the refrigerator between 36°f to 46°f (2°c to 8°c). you may store voxzogo (before mixing) at room temperature between 68°f to 77°f (20°c to 25°c) for 90 days. record the date you started storing voxzogo at room temperature on the carton to keep track of the 90 days. do not return voxzogo to the refrigerator after it has been stored at room temperature. throw voxzogo away if unused within 90 days of storing at room temperature. do not use voxzogo past the expiration date. do not freeze voxzogo. store voxzogo out of direct sunlight. keep voxzogo and all medicines out of the reach of children. general information about the safe and effective use of voxzogo. medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. do not use voxzogo for a condition for which it was not prescribed. do not give voxzogo to other people, even if they have the same symptoms you have. it may harm them. you can ask your pharmacist or healthcare provider for information about voxzogo that is written for health professionals. what are the ingredients in voxzogo? active ingredient: vosoritide inactive ingredients : trehalose dihydrate, mannitol, sodium citrate dihydrate, methionine, citric acid monohydrate, and polysorbate 80 biomarin pharmaceutical inc. novato, ca 94949 © biomarin pharmaceutical inc. all rights reserved. voxzogo is a registered trademark of biomarin pharmaceutical inc. for more information, go to www.voxzogo.com or call 1-877-695-8826.