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CRYSVITA is a brand name for Burosumab. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: 1 INDICATIONS AND USAGE 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…
Verbatim from this product's FDA label. Tap a section to expand.
8 mg/kg of body weight rounded to the nearest 10 mg, administered every two weeks. The minimum starting dose is 10 mg up to a maximum dose of 90 mg. 2 ) Dose may be increased up to approximately 2 mg/kg (maximum 90 mg), administered every two weeks to achieve normal serum phosphorus.
2 ) Adult XLH: Dose regimen is 1 mg/kg body weight rounded to the nearest 10 mg up to a maximum dose of 90 mg administered every four weeks. 4 mg/kg of body weight rounded to the nearest 10 mg every 2 weeks. Dose may be increased up to 2 mg/kg not to exceed 180 mg, administered every two weeks.
5 mg/kg every four weeks. Dose may be increased up to 2 mg/kg not to exceed 180 mg, administered every two weeks. g. 3) ] . Prior to starting CRYSVITA, fasting serum phosphorus concentration should be below the reference range for age [see Contraindications (4) ].
3) ] . CRYSVITA is administered by subcutaneous injection and should be administered by a healthcare provider. 5 mL. If multiple injections are required, administer at different injection sites. 2 Recommended Dosage for Pediatric Patients with X-linked Hypophosphatemia (6 months to less than 18 years of age) For patients who weigh less than 10 kg, the recommended starting dosage is 1 mg/kg of body weight, rounded to the nearest 1 mg, administered every two weeks.
8 mg/kg of body weight, rounded to the nearest 10 mg, administered every two weeks. The minimum starting dose is 10 mg up to a maximum dose of 90 mg. After initiation of treatment with CRYSVITA, measure fasting serum phosphorus every 4 weeks for the first 3 months of treatment, and thereafter as appropriate.
If serum phosphorus is above the lower limit of the reference range for age and below 5 mg/dL, continue treatment with the same dose. Follow dose adjustment schedule below to maintain serum phosphorus within the reference range for age.
Dose Adjustment Reassess fasting serum phosphorus level 4 weeks after dose adjustment. Do not adjust CRYSVITA more frequently than every 4 weeks. 5 mg/kg, rounded to the nearest 1 mg, administered every two weeks. If additional dose increases are needed, the dose may be increased to the maximum dose of 2 mg/kg, rounded to the nearest 1 mg, administered every two weeks.
For patients who weigh 10 kg or greater, if serum phosphorus is below the reference range for age, the dose may be increased stepwise up to approximately 2 mg/kg, administered every two weeks (maximum dose of 90 mg) according to the dosing schedule shown in Table 1.
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. 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.
1 ) Most common adverse reactions (>10%) in TIO patients are: tooth abscess, muscle spasms, dizziness, constipation, injection site reaction, rash, and headache. 1 ) To report SUSPECTED ADVERSE REACTIONS, contact Kyowa Kirin, Inc. gov/medwatch .
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.
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). 0 years), 49% male, and 88% white. 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 .
5 WARNINGS AND PRECAUTIONS Hypersensitivity : Discontinue CRYSVITA if serious hypersensitivity reactions occur and initiate appropriate medical treatment. 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.
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. 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. g. rash, urticaria) have been reported in patients with CRYSVITA. 1) ] . 2 Hyperphosphatemia 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. 1) ] . 3 Hypercalcemia 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. 4 Injection Site Reactions Administration of CRYSVITA may result in local injection site reactions. 1) ] .
g. 1) ] . 2) ] . 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 )
Not medical advice. Always read the patient information leaflet and follow your prescriber or pharmacist.
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Table 1:
XLH Pediatric Dose Schedule for Stepwise Dose Increase for Patients Weighing 10 kg or More Body Weight (kg) Starting Dose (mg) First Dose Increase to (mg) Second Dose Increase to (mg) 10 – 14 10 15 20 15 – 18 10 20 30 19 – 31 20 30 40 32 – 43 30 40 60 44 – 56 40 60 80 57 – 68 50 70 90 69 – 80 60 90 90 81 – 93 70 90 90 94 – 105 80 90 90 106 and greater 90 90 90 Dose Decrease: If serum phosphorus is above 5 mg/dL, withhold the next dose and reassess the serum phosphorus level in 4 weeks.
The patient must have serum phosphorus below the reference range for age to reinitiate CRYSVITA. Once serum phosphorus is below the reference range for age, treatment may be restarted. 5 mg/kg of body weight, rounded to the nearest 1 mg, administered every two weeks.
For patients who weigh 10 kg or more, restart CRYSVITA according to the dose schedule shown in Table 2.
Table 2:
XLH Pediatric Dose Schedule for Re-Initiation of Therapy for Patients Weighing 10 kg or More Previous Dose (mg) Re-Initiation Dose (mg) 10 5 15 10 20 10 30 10 40 20 50 20 60 30 70 30 80 40 90 40 After a dose decrease, reassess serum phosphorus level 4 weeks after the dose adjustment.
If the level remains below the reference range for age after the re-initiation dose, the dose can be adjusted as outlined under Dose Increase. 3 Recommended Dosage for Adult Patients with X-linked Hypophosphatemia (18 years of age and older) The recommended dosage regimen in adults is 1 mg/kg body weight, rounded to the nearest 10 mg up to a maximum dose of 90 mg, administered every four weeks.
After initiation of treatment with CRYSVITA, assess fasting serum phosphorus on a monthly basis, measured 2 weeks post-dose, for the first 3 months of treatment, and thereafter as appropriate. If serum phosphorus is within the normal range, continue with the same dose.
Dose Decrease Reassess fasting serum phosphorus level 2 weeks after dose adjustment. Do not adjust CRYSVITA more frequently than every 4 weeks. If serum phosphorus is above the normal range, withhold the next dose and reassess the serum phosphorus level after 4 weeks.
The patient must have serum phosphorus below the normal range to be able to reinitiate CRYSVITA. Once serum phosphorus is below the normal range, treatment may be restarted at approximately half the initial starting dose up to a maximum dose of 40 mg every 4 weeks according to the dose schedule shown in Table 3.
Reassess serum phosphorus 2 weeks after any change in dose. 4 mg/kg body weight administered every 2 weeks, rounded to the nearest 10 mg, up to a maximum dose of 2 mg/kg not to exceed 180 mg, administered every 2 weeks. After initiation of treatment with CRYSVITA, assess fasting serum phosphorus on a monthly basis, measured 2 weeks post-dose, for the first 3 months of treatment, and thereafter as appropriate.
If serum phosphorus is within the reference range for age, continue with the same dose. Follow the dose adjustment schedule below to maintain serum phosphorus within the reference range for age. Dose Adjustment Reassess fasting serum phosphorus level 4 weeks after dose adjustment.
Do not adjust CRYSVITA more frequently than every 4 weeks. Dose Increase If serum phosphorus is below the reference range for age, the dose should be titrated in accordance with Table 4 up to the maximum dose of 2 mg/kg every 2 weeks.
The maximum dose should not exceed 180 mg. 5 mg/kg. Further dose increases to a maximum of 2 mg/kg not to exceed 180 mg, administered every 2 weeks should be calculated by the physician. Increase to (mg) 10 – 14 5 10 15 20 15 – 18 5 10 20 25 19 – 31 10 20 25 30 32 – 43 10 30 40 50 44 – 56 20 40 50 70 57 – 68 20 50 70 90 69 – 80 30 60 80 100 81 – 93 30 70 100 120 94 – 105 40 80 110 140 106 and greater 40 90 130 160 Dose Decrease If serum phosphorus is above the reference range for age, withhold the next dose and reassess the serum phosphorus level in 4 weeks.
The patient must have serum phosphorus below the reference range for age to reinitiate CRYSVITA. Once serum phosphorus is below the reference range for age, treatment may be restarted at approximately half the initial starting dose, up to a maximum dose of 180 mg administered every 2 weeks for pediatrics.
After a dose decrease, reassess serum phosphorus level 4 weeks after the dose adjustment. If the level remains below the reference range for age after the re-initiation dose, the dose can be adjusted as outlined per Table 4 . , surgical excision or radiation therapy) CRYSVITA treatment should be interrupted and serum phosphorus reassessed after treatment has been completed.
CRYSVITA dose should be restarted at the patient's initiation dose if serum phosphorus remains below the lower limit of normal. Follow dose adjustment per Table 4 to maintain serum phosphorus within the reference range for age. 5 mg/kg body weight administered every 4 weeks, rounded to the nearest 10 mg, up to a maximum dose of 2 mg/kg not to exceed 180 mg, administered every 2 weeks.
After initiation of treatment with CRYSVITA, assess fasting serum phosphorus on a monthly basis, measured 2 weeks post-dose, for the first 3 months of treatment, and thereafter as appropriate. If serum phosphorus is within the normal range, continue with the same dose.
Follow the dose adjustment schedule below to maintain serum phosphorus within the reference range. Dose Adjustment Reassess fasting serum phosphorus level 2 weeks after dose adjustment. Do not adjust CRYSVITA more frequently than every 4 weeks.
Dose Increase If serum phosphorus is below the normal range, the dose should be titrated in accordance with Table 5 up to the maximum dose of 2 mg/kg not to exceed 180 mg, administered every 2 weeks. For those individuals not reaching a serum phosphorus greater than the lower limit of the normal range, physicians may consider dividing total dose administered every 4 weeks and administering every 2 weeks.
Table 5:
TIO Dose Schedule Rounded to the nearest 10 mg. for Stepwise Do not adjust CRYSVITA more frequently than every 4 weeks. Dose Increase for Adults (18 years of age and older) Starting Dose First Dose Increase For those individuals not reaching a serum phosphorus greater than the lower limit of the normal range, physicians may consider dividing total dose administered every 4 weeks and administering every 2 weeks.
5 mg/kg every 4 weeks In patients with high body weight, if the calculated dose is greater than 180 mg every 4 weeks, move to a divided dose every 2 weeks. 5 mg/kg not to exceed 180 mg every 2 weeks Increase to: 2 mg/kg not to exceed 180 mg every 2 weeks Dose Decrease If serum phosphorus is above the normal range, withhold the next dose and reassess the serum phosphorus level in 4 weeks.
The patient must have serum phosphorus below the reference range to reinitiate CRYSVITA. Once serum phosphorus is below the reference range, treatment may be restarted at approximately half the initial starting dose, up to a maximum dose of 180 mg administered every 2 weeks for adults.
After a dose decrease, reassess serum phosphorus level 2 weeks after the dose adjustment. If the level remains below the reference range after the re-initiation dose, the dose can be adjusted as outlined per Table 5 . , surgical excision or radiation therapy) CRYSVITA treatment should be interrupted and serum phosphorus reassessed after treatment has been completed.
CRYSVITA dose should be restarted at the patient’s initiation dose if serum phosphorus remains below the lower limit of normal. Follow dose adjustment per Table 5 to maintain serum phosphorus within the reference range. 6 Missed Dose If a patient misses a dose, resume CRYSVITA as soon as possible at the prescribed dose.
To avoid missed doses, treatments may be administered 3 days either side of the scheduled treatment date. 7 25-Hydroxy Vitamin D Supplementation Monitor 25-hydroxy vitamin D levels. Supplement with cholecalciferol or ergocalciferol to maintain 25-hydroxy vitamin D levels in the normal range for age.
Do not administer active Vitamin D analogs during CRYSVITA treatment [see Contraindications (4) ]. 8 General Considerations for Subcutaneous Administration Injection sites should be rotated with each injection administered at a different anatomic location (upper arms, upper thighs, buttocks, or any quadrant of abdomen) than the previous injection.
Do not inject into moles, scars, or areas where the skin is tender, bruised, red, hard, or not intact. If a given dose on a dosing day requires multiple vials of CRYSVITA, contents from two vials can be combined for injection. 5 mL. If multiple injections are required on a given dosing day, administer at different injection sites.
4) ] . Visually inspect CRYSVITA for particulate matter and discoloration prior to administration. CRYSVITA is a sterile, preservative-free, clear to slightly opalescent and colorless to pale brown-yellow solution for subcutaneous injection.
Do not use if the solution is discolored or cloudy or if the solution contains any particles or foreign particulate matter.
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. 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. 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. 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 syndrome 8 (12) 5 (8) Vitamin D decreased Vitamin D decreased includes: vitamin D deficiency, blood 25-hydroxycholecalciferol decreased, and vitamin D decreased 8 (12) 3 (5) Dizziness 7 (10) 4 (6) Muscle spasms 5 (7) 2 (3) Constipation 6 (9) 0 (0) Blood phosphorus increased Blood phosphorus increased includes: blood phosphorus increased, and hyperphosphatemia 4 (6) 0 (0) The 24-week placebo controlled study was followed by a 24-week open-label treatment period in which all patients received CRYSVITA subcutaneously every 4 weeks.
No new adverse reactions were identified in the open-label extension period. Hypersensitivity Reactions In the double-blind period of Study 4, approximately 6% of patients in both the CRYSVITA and placebo treatment groups experienced a hypersensitivity event.
The events were mild or moderate and did not require discontinuation. 5 mg/dL [the upper limit of normal] on two occasions). The hyperphosphatemia was managed with dose reduction. The dose for all patients meeting the protocol-specified criteria was reduced 50 percent.
A single patient required a second dose reduction for continued hyperphosphatemia. g. injection site reaction, erythema, rash, bruising, pain, pruritus, and hematoma) at the site of the 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.
Restless Legs Syndrome (RLS) In the double-blind period of Study 4, approximately 12% of the CRYSVITA treatment group had worsening of baseline restless legs syndrome (RLS) or new onset RLS of mild to moderate severity; these events did not lead to dose discontinuation.
Nonserious RLS has also been reported in other repeat dose adult XLH studies; in one case, worsening baseline RLS led to drug discontinuation and subsequent resolution of the event. Spinal Stenosis Spinal stenosis is prevalent in adults with XLH and spinal cord compression has been reported.
In the CRYSVITA phase 2 and phase 3 studies of adults with XLH (total N=176), a total of 7 patients underwent spinal surgery. Most of these cases appeared to involve progression of a pre-existing spinal stenosis. It is unknown if CRYSVITA therapy exacerbates spinal stenosis or spinal cord compression.
Adverse Reactions in Patients with TIO The safety of CRYSVITA in patients with TIO was demonstrated in two single-arm clinical studies (Study 6 and Study 7) that enrolled a total of 27 patients. Fourteen patients were male, and patients ranged from 33 to 73 years of age.
77 mg/kg every 4 weeks and the mean duration of exposure was 121 weeks. Adverse reactions reported in adult TIO patients in the pooled data from Study 6 and Study 7 are shown in Table 9 .
Table 9:
Adverse Reactions Reported in Adult Patients with TIO Based on Study 6 and Study 7 (N=27) Adverse Reaction Overall (N=27) n (%) Tooth abscess Tooth abscess is defined by PTs "Tooth abscess" and "Tooth ache" 5 (19) Muscle spasms 5 (19) Dizziness 4 (15) Constipation 4 (15) Injection site reaction Injection Site Reactions is defined by PTs "Injection Site Reaction", "Injection Site Pain" and "Injection Site Swelling" 4 (15) Rash Rash is defined by PTs "Rash" and "Rash papular" 4 (15) Headache 3 (11) Vitamin D deficiency 2 (7) Hyperphosphatemia 2 (7) Restless legs syndrome 2 (7) Hypersensitivity reactions In the pooled data for Studies 6 and 7, 22% of patients experienced a hypersensitivity reaction.
The most frequent hypersensitivity reactions were eczema (11%) and rash (11%). The events were mild or moderate in severity. Hyperphosphatemia In the pooled data for Studies 6 and 7, 2 patients (7%) experienced hyperphosphatemia which was managed with dose reduction.
Injection site reactions The frequency of injection site reactions was 15% (injection site reaction, injection site pain, and injection site swelling). The injection site reactions were generally mild in severity, required no treatment and resolved in all cases.
Restless Legs Syndrome In the pooled data for Studies 6 and 7, 2 patients (7%) experienced symptoms of restless legs syndrome, which were mild and did not require treatment interruption. 2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of CRYSVITA.
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Metabolism and nutrition disorders:
Hypercalcemia Skin and subcutaneous tissue disorders: Urticaria Investigations: Blood phosphorus increased in pediatric XLH patients, blood parathyroid hormone increased