Crysvita Drug Information

X-linked Hypophosphatemia CRYSVITA is indicated for the treatment of X-linked hypophosphatemia (XLH) in adult and pediatric patients 6 months of age and older.

Tumor-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.

Important Information Prior to Initiation of CRYSVITA Prior to starting CRYSVITA, discontinue oral phosphate and/or active vitamin D analogs (e.g. calcitriol, paricalcitol, doxercalciferol, calcifediol) for one week. Prior to starting CRYSVITA, fasting serum phosphorus concentration should be below the reference range for age. In patients at high risk for hypercalcemia (e.g., pre-existing hyperparathyroidism, prolonged immobilization, dehydration, hypervitaminosis D, or renal impairment) assess serum calcium and parathyroid hormone levels prior to starting CRYSVITA.

CRYSVITA is administered by subcutaneous injection and should be administered by a healthcare provider. The maximum volume of CRYSVITA per injection is 1.5 mL. If multiple injections are required, administer at different injection sites.

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. For patients who weigh 10 kg and greater, the recommended starting dose regimen is 0.8 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. Dose Increase: For patients who weigh less than 10 kg, if serum phosphorus is below the reference range for age, the dose may be increased to 1.5 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. Table 1: XLH Pediatric Dose Schedule for Stepwise Dose Increase for Patients Weighing 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. For patients who weigh less than 10 kg, restart CRYSVITA at 0.5 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. 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.

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. If serum phosphorus is not within the normal range, follow the dosage modification schedule below.

Dose Adjustment CRYSVITA dosage may be decreased at any time for elevated serum phosphorus. CRYSVITA dosage may be increased after initial 3 months of treatment to maintain serum phosphorus within the normal range. Reassess fasting serum phosphorus level 2 weeks after dosage adjustment.

Dose Increase If serum phosphorus is below the normal range after the initial treatment period, patients may be transitioned to a CRYSVITA dosage of 0.5 mg/kg, not to exceed 90 mg, once every 2 weeks. Dose Decrease 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 previous dose. Reassess serum phosphorus 2 weeks after any change in dose. 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. Table 4: TIO Pediatric Dose Schedule for Stepwise Dose Increase for Patients Weighing 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. Dose Interruption If a patient undergoes treatment of the underlying tumor (i.e., 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. 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.

Follow dose adjustment per Table 5 to maintain serum phosphorus within the reference range.

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. 2.7 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.

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.

Monitor for signs of reactions. 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.

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. 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. The mean duration of exposure in Study 2 was 124 weeks. The mean duration of exposure in Study 3 was 45 weeks.

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. A total of 68 and 66 patients received at least one dose of CRYSVITA or placebo, respectively. 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. Hyperphosphatemia In the double-blind period of Study 4, 7% of patients in the CRYSVITA treatment group experienced hyperphosphatemia meeting the protocol-specified criteria for dose reduction (either a single serum phosphorus greater than 5.0 mg/dL or serum phosphorus greater than 4.5 mg/dL 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.

Injection Site Reactions (ISR) In the double-blind period of Study 4, approximately 12% of patients in both the CRYSVITA and placebo treatment groups had a local reaction (e.g. injection site reaction, erythema, rash, bruising, pain, pruritus, and hematoma) at the site of the injection. 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.

The mean dose of CRYSVITA was 0.77 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. The most frequent hypersensitivity reactions were eczema (11%) and rash (11%).

The events were mild or moderate in severity. 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.

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

Oral 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 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. 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.

Pediatric Use Safety and effectiveness of CRYSVITA have been established in pediatric patients 6 months and older. Safety and effectiveness in pediatric patients 1 year and older with XLH are based on one phase 3, open-label, active control study and two open-label studies evaluating serum phosphorus and radiographic findings. Safety and effectiveness in patients 6 months to 1 year and adolescents are supported by evidence from the studies in pediatric patients 1 year to less than 13 years of age with additional modeling and simulation of adult and pediatric pharmacokinetic (PK) and pharmacodynamic (PD) data to inform dosing.

Safety and effectiveness for CRYSVITA in pediatric patients with XLH below the age of 6 months have not been established. Safety and effectiveness of CRYSVITA in pediatric patients 2 years and older with TIO are supported by evidence from the studies in adult patients with TIO with additional modeling and simulation of PK data from adult and pediatric XLH patients and adult TIO patients to inform dosing. Safety and effectiveness for CRYSVITA in pediatric patients with TIO below the age of 2 years have not been established.

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. When serum phosphorus is within or above the normal range for age. In patients with severe renal impairment or end stage renal disease because these conditions are associated with abnormal mineral metabolism.

There have been no reports of overdose with CRYSVITA. CRYSVITA has been administered in pediatric clinical trials without dose limiting toxicity using doses up to 2 mg/kg body weight with a maximal dose of 90 mg, administered every two weeks. In XLH adult clinical trials, no dose limiting toxicity has been observed using doses up to 1 mg/kg or a maximal total dose of 128 mg every 4 weeks.

In non-XLH rabbits and cynomolgus monkeys, ectopic mineralization in multiple tissues and organs was observed at doses of burosumab-twza that resulted in supra-physiologic serum phosphate levels. Adverse effects on bone including reductions in bone mineral density, bone mineralization and bone strength were also observed at exposure greater than human exposure. In case of overdose, it is recommended that serum phosphorus levels, serum calcium levels and renal function be measured immediately and monitored periodically until resolution to normal/baseline levels.

In case of hyperphosphatemia, withhold CRYSVITA and initiate appropriate medical treatment.