CRYSVITA is a fibroblast growth factor 23 (FGF23) blocking antibody indicated for: The treatment of X-linked hypophosphatemia (XLH) in adult and pediatric patients 6 months of age and older. ( 1.1 ) The treatment of FGF23-related hypophosphatemia in tumor-induced osteomalacia (TIO) associated with phosphaturic mesenchymal tumors that cannot be curatively resected or localized in adult and pediatric patients 2 years of age and older.
( 1.2 )
1.1X-linked Hypophosphatemia
CRYSVITA is indicated for the treatment of X-linked hypophosphatemia (XLH) in adult and pediatric patients 6 months of age and older.
1.2Tumor-induced Osteomalacia
CRYSVITA is indicated for the treatment of FGF23-related hypophosphatemia in tumor-induced osteomalacia (TIO) associated with phosphaturic mesenchymal tumors that cannot be curatively resected or localized in adult and pediatric patients 2 years of age and older.
Contraindications
CRYSVITA is contraindicated: In concomitant use with oral phosphate and/or active vitamin D analogs (e.g. calcitriol, paricalcitol, doxercalciferol, calcifediol) due to the risk of hyperphosphatemia [see Warnings and Precautions (5.2) and Drug Interactions (7.1) ] . When serum phosphorus is within or above the normal range for age [see Warnings and Precautions (5.2) ] . In patients with severe renal impairment or end stage renal disease because these conditions are associated with abnormal mineral metabolism [see Use In Specific Population (8.6) ] .
With oral phosphate and/or active vitamin D analogs. ( 4 ) When serum phosphorus is within or above the normal range for age. ( 4 ) In patients with severe renal impairment or end stage renal disease. ( 4 )
Warnings and precautions
Hypersensitivity : Discontinue CRYSVITA if serious hypersensitivity reactions occur and initiate appropriate medical treatment. ( 5.1 ) Hyperphosphatemia and Risk of Nephrocalcinosis : For patients already taking CRYSVITA, dose interruption and/or dose reduction may be required based on a patient's serum phosphorus levels. ( 5.2 , 6.1 ) Hypercalcemia : Increases in serum calcium been reported. Monitor serum calcium and parathyroid hormone levels in patients at high risk for hypercalcemia before and during treatment.
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( 5.3 ) Injection Site Reactions : Administration of CRYSVITA may result in local injection site reactions. Discontinue CRYSVITA if severe injection site reactions occur and administer appropriate medical treatment. ( 5.4 , 6.1 )
5.1Hypersensitivity
Hypersensitivity reactions (e.g. rash, urticaria) have been reported in patients with CRYSVITA. Discontinue CRYSVITA if serious hypersensitivity reactions occur and initiate appropriate medical treatment [see Adverse Reactions (6.1) ] .
5.2Hyperphosphatemia and Risk of Nephrocalcinosis Increases
in serum phosphorus to above the upper limit of normal may be associated with an increased risk of nephrocalcinosis. For patients already taking CRYSVITA, dose interruption and/or dose reduction may be required based on a patient's serum phosphorus levels. Patients with tumor-induced osteomalacia who undergo treatment of the underlying tumor should have dosing interrupted and adjusted to prevent hyperphosphatemia [see Dosage and Administration (2) and Adverse Reactions (6.1) ] .
5.3Hypercalcemia Increases
in serum calcium have been reported in patients treated with CRYSVITA. Patients with risk factors such as, pre-existing hyperparathyroidism, prolonged immobilization, dehydration, hypervitaminosis D, or renal impairment, are at higher risk of hypercalcemia. Monitor these patients for serum calcium and parathyroid hormone levels before and during CRYSVITA treatment for moderate to severe hypercalcemia. In patients with moderate to severe hypercalcemia, CRYSVITA should not be administered until hypercalcemia is adequately managed.
5.4Injection Site Reactions Administration of
CRYSVITA may result in local injection site reactions. Discontinue CRYSVITA if severe injection site reactions occur and administer appropriate medical treatment [see Adverse Reactions (6.1) ] .
Interactions
7.1Oral Phosphate and Active Vitamin D Analogs
Concomitant use of CRYSVITA with oral phosphate and/or active vitamin D analogs will increase phosphate concentrations greater than expected with CRYSVITA alone. This increase may result in hyperphosphatemia which can induce nephrocalcinosis. Concomitant use of CRYSVITA with oral phosphate and/or active vitamin D analogs is contraindicated.
Pregnancy and breastfeeding
8.1Pregnancy Risk Summary
There are no available data on CRYSVITA use in pregnant women to inform a drug-associated risk of adverse developmental outcomes. In utero, burosumab-twza exposure in cynomolgus monkeys did not result in teratogenic effects. Adverse effects such as late fetal loss and preterm birth were observed in pregnant cynomolgus monkeys, however, these effects are unlikely to indicate clinical risk because they occurred at a drug exposure that was 15-fold higher, by AUC, than the human exposure at the maximum recommended human dose (MRHD) of 2 mg/kg every 2 weeks and were accompanied by maternal hyperphosphatemia and placental mineralization ( see Data ).
Serum phosphorus levels should be monitored throughout pregnancy [see Dosage and Administration (2.2) ]. Report pregnancies to the Kyowa Kirin, Inc. Adverse Event reporting line at 1-844-768-3544. The background risk of major birth defects and miscarriage for the indicated population is unknown; however, the estimated background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.
Data Animal Data In a reproductive toxicity study in pregnant cynomolgus monkeys, burosumab-twza was administered intravenously once every two weeks from Day 20 of pregnancy to parturition or cesarean section on Day 133, which includes the period of organogenesis, at doses of 0.2-, 2- and 15-fold human exposure at the adult MRHD of 2 mg/kg every 2 weeks. The treatment did not result in teratogenic effects in fetuses or offspring.
An increase in late fetal loss, a shortened gestation period, and an increased incidence of preterm births were observed at 15-fold human exposure at the adult MRHD of 2 mg/kg every 2 weeks, concomitant with maternal hyperphosphatemia and placental mineralization. Burosumab-twza was detected in serum from fetuses indicating transport across the placenta. Hyperphosphatemia but no ectopic mineralization was present in fetuses and offspring of dams exposed to 15-fold human exposure at the MRHD of 2 mg/kg dose every 2 weeks.
Burosumab-twza did not affect pre- and postnatal growth including survivability of the offspring.
Adverse reactions
The following adverse reactions are described below and elsewhere in the labeling: Hypersensitivity [see Warnings and Precautions (5.1) ] Hyperphosphatemia and Risk of Nephrocalcinosis [see Warnings and Precautions (5.2) ] Hypercalcemia [see Warnings and Precautions (5.3) Injection Site Reactions [see Warnings and Precautions (5.4) ] Most common adverse reactions (≥25% in the CRYSVITA group and > Active Control) in pediatric XLH patients are: pyrexia, injection site reaction, cough, vomiting, pain in extremity, headache, tooth abscess, dental caries.
( 6.1 ) Most common adverse reactions (>5% and in at least 2 patients more than placebo) in adult XLH patients are: back pain, headache, tooth infection, restless legs syndrome, vitamin D decreased, dizziness, constipation, muscle spasms, blood phosphorus increased. ( 6.1 ) Most common adverse reactions (>10%) in TIO patients are: tooth abscess, muscle spasms, dizziness, constipation, injection site reaction, rash, and headache.
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Kyowa Kirin, Inc. at 1-844-768-3544 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. Adverse Reactions in Pediatric Patients with XLH CRYSVITA was studied in three pediatric XLH studies. Study 1 is a randomized, open-label phase 3 study in XLH patients ages 1 to 12 years, who were randomized to treatment with CRYSVITA or treatment with active control of oral phosphate and active vitamin D (CRYSVITA N = 29, Active Control N = 32).
Study 2 is an open-label phase 2 study in XLH patients ages 5 to 12 years (N = 52). Study 3 is an open-label phase 2 study in XLH patients ages 1 to less than 5 years (N = 13). Overall, the patient population was 1-12 years (mean age 7.0 years), 49% male, and 88% white. In Study 1, patients randomized to CRYSVITA received a mean dose of approximately 0.90 mg/kg (range 0.8-1.2 mg/kg) every 2 weeks. All patients in this group and the active control group completed 64 weeks of treatment.
Adverse reactions occurring in ≥ 10% of subjects in the CRYSVITA group, with higher frequency than in the subjects in the active control group, through the 64-week treatment period in Study 1 are shown in Table 6 . Table 6: Adverse Reactions Reported in 10% or More of CRYSVITA-Treated Pediatric Patients and with Higher Frequency Than the Active Control Group in Study 1 Adverse Reaction CRYSVITA (N=29) n (%) Active Control (N=32) n (%) n = number of patients with an event; N = total number of patients who received at least one dose of CRYSVITA or active control Pyrexia 16 (55) 6 (19) Injection site reaction Injection site reaction includes: injection site reaction, injection site erythema, injection site pruritus, injection site swelling, injection site pain, injection site rash, injection site bruising, injection site discoloration, injection site discomfort, injection site hematoma, injection site hemorrhage, injection site induration, injection site macule, and injection site urticaria 15 (52) 0 (0) Cough Cough includes: cough and productive cough 15 (52) 6 (19) Vomiting 12 (41) 8 (25) Pain in extremity 11 (38) 10 (31) Headache 10 (34) 6 (19) Tooth abscess Tooth abscess includes: tooth abscess, tooth infection, toothache 10 (34) 4 (13) Dental caries 9 (31) 2 (6) Diarrhea 7 (24) 2 (6) Vitamin D decreased Vitamin D decreased includes: vitamin D deficiency, blood 25-hydroxycholecalciferol decreased, and vitamin D decreased 7 (24) 1 (3) Constipation 5 (17) 0 (0) Rash Rash includes: rash, rash pruritic, rash maculopapular, rash erythematous, rash generalized and rash pustular 4 (14) 2 (6) Nausea 3 (10) 1 (3) In Study 2, 26 of the patients received CRYSVITA at a mean dose of 1.05 mg/kg (range 0.4 – 2.0 mg/kg) every 2 weeks at Week 64; the other 26 patients received CRYSVITA every 4 weeks.
The mean duration of exposure in Study 2 was 124 weeks. In Study 3, patients received CRYSVITA at a mean dose of 0.90 mg/kg (range 0.8-1.2 mg/kg) every 2 weeks at Week 40. The mean duration of exposure in Study 3 was 45 weeks. Adverse reactions occurring in more than 10% of CRYSVITA-treated patients from Studies 2 and 3 are shown in Table 7 . Table 7: Adverse Reactions Reported in More Than 10% of Pediatric Patients Receiving CRYSVITA in Studies 2 and 3 Adverse Reaction Study 2 (N=52) n (%) Study 3 (N=13) n (%) Overall (N=65) n (%) n = number of patients with an event; N = total number of patients who received at least one dose of CRYSVITA Headache 38 (73) 1 (8) 39 (60) Injection site reaction Injection site reaction includes: injection site reaction, injection site erythema, injection site pruritus, injection site swelling, injection site pain, injection site rash, injection site bruising, injection site discoloration, injection site discomfort, injection site hematoma, injection site hemorrhage, injection site induration, injection site macule, and injection site urticaria 35 (67) 3 (23) 38 (59) Vomiting 25 (48) 6 (46) 31 (48) Pyrexia 23 (44) 8 (62) 31 (48) Pain in extremity 24 (46) 3 (23) 27 (42) Vitamin D decreased Vitamin D decreased includes: vitamin D deficiency, blood 25-hydroxycholecalciferol decreased, and vitamin D decreased 19 (37) 2 (15) 21 (32) Rash Rash includes: rash, rash pruritic, rash maculopapular, and rash pustular 14 (27) 1 (8) 15 (23) Toothache 12 (23) 2 (15) 14 (22) Myalgia 9 (17) 1 (8) 10 (15) Tooth abscess 8 (15) 3 (23) 11 (17) Dizziness Dizziness includes: dizziness, and dizziness exertional 8 (15) 0 (0) 8 (12) Hypersensitivity Reactions In Study 1 (N=29 for CRYSVITA arm), the most frequent hypersensitivity reactions were rash (10%), injection site rash (10%) and injection site urticaria (7%).
In Studies 2 and 3 (N=65), the most frequent hypersensitivity reactions were rash (22%), injection site rash (6%), and urticaria (5%). Hyperphosphatemia In pediatric studies, no events of hyperphosphatemia were reported. Injection Site Reactions (ISR) In Study 1 (N=29 for CRYSVITA arm), 52% of the patients had a local injection site reaction (e.g. injection site urticaria, erythema, rash, swelling, bruising, pain, pruritus, and hematoma) at the site of CRYSVITA injection.
In Studies 2 and 3 (N=65), approximately 58% of the patients had a local injection site reaction at the site of CRYSVITA injection. Injection site reactions were generally mild in severity, occurred within 1 day of injection, lasted approximately 1 to 3 days, required no treatment, and resolved in almost all instances. Adverse Reactions in Adult Patients with XLH The safety of CRYSVITA in adult patients with XLH was demonstrated in a randomized, double-blind, placebo-controlled study (Study 4) of 134 patients, age 20-63 years (mean age 41 years), of whom most were white/Caucasian (81%) and female (65%).
A total of 68 and 66 patients received at least one dose of CRYSVITA or placebo, respectively. The mean dose of CRYSVITA was 0.95 mg/kg (range 0.3 – 1.2 mg/kg) subcutaneously every 4 weeks. Adverse reactions reported in more than 5% of CRYSVITA-treated patients and 2 patients or more than with placebo from the 24-week placebo-controlled portion of Study 4 are shown in Table 8 . Table 8: Adverse Reactions Occurring in More Than 5% of CRYSVITA-Treated Adult Patients and in at Least 2 Patients More Than with Placebo in the 24-Week Placebo-Controlled Period of Study 4 Adverse Reaction CRYSVITA (N=68) n (%) Placebo (N=66) n (%) n = number of patients with an event; N = total number of patients who received at least one dose of CRYSVITA or placebo Back pain 10 (15) 6 (9) Headache Headache includes: headache, and head discomfort 9 (13) 6 (9) Tooth infection Tooth infection includes: tooth abscess, and tooth infection 9 (13) 6 (9) Restless legs syndrom
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Composition
Active ingredients
BUROSUMAB-TWZA 10MG/ML
Official product information
Drugs@FDA lists the approved labels, letters and reviews for application BLA761068.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
At a glance
Brand name
Crysvita
Active substance
burosumab-twza
Drug class
Other drugs affecting bone structure and mineralization
