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Burosumab-twza

Class: Electrolytic, Caloric, and Water Balance Agents; Miscellaneous
Brands: Crysvita

Medically reviewed by Drugs.com. Last updated on May 7, 2018.

Introduction

Burosumab-twza is a recombinant DNA-derived human immunoglobulin G1 (IgG1) antibody specific for human fibroblast growth factor 23 (FGF23).1

Uses for Burosumab-twza

Burosumab-twza has the following uses:

Burosumab-twza is indicated for the treatment of X-linked hypophosphatemia (XLH) in adult and pediatric patients 1 year of age and older.1

Burosumab-twza Dosage and Administration

General

Burosumab-twza is available in the following dosage form(s) and strength(s):

Injection: 10 mg/mL, 20 mg/mL, or 30 mg/mL in a single-dose vial.1

Dosage

Burosumab-twza is administered by subcutaneous injection and should be administered by a healthcare provider.1

Discontinue oral phosphate and active vitamin D analogs 1 week prior to initiation of treatment. Fasting serum phosphorus concentration should be below the reference range for age prior to initiation of treatment.1

Pediatric Patients

Pediatric Patients With X-Linked Hypophosphatemia (1 To Less Than 18 Years Of Age)

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.1

After initiation of treatment with burosumab-twza, 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.1

Dose Adjustment

Reassess fasting serum phosphorus level 4 weeks after dose adjustment.1

Do not adjust burosumab-twza more frequently than every 4 weeks.1

Dose Increase: 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 1.1

Table 1: Pediatric Dose Schedule for Stepwise Dose Increase

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 burosumab-twza. Once serum phosphorus is below the reference range for age, treatment may be restarted according to the dose schedule shown in Table 2. Reassess serum phosphorus level 4 weeks after dose adjustment. If the level remains below the reference range for age after the re-initiation dose, the dose can be adjusted according to Table 1.1

Table 2: Pediatric Dose Schedule for Re-Initiation of Therapy

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

Adults

Adult Patients With X-Linked Hypophosphatemia (18 Years Of Age And Older)

The recommended dose regimen in adults is 1 mg/kg of body weight, rounded to the nearest 10 mg up to a maximum dose of 90 mg, administered every four weeks.1

After initiation of treatment with burosumab-twza, 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.1

Dose Decrease: Reassess fasting serum phosphorus level 2 weeks after dose adjustment.1

Do not adjust burosumab-twza more frequently than every 4 weeks.1

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 burosumab-twza. 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.1

Table 3: Adult Dose Schedule for Re-Initiation of Therapy

Previous Dose (mg)

Re-Initiation Dose (mg)

40

20

50

20

60

30

70

30

80 and greater

40

Missed Dose

If a patient misses a dose, resume burosumab-twza as soon as possible at the prescribed dose.1

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. The maximum volume of burosumab-twza per injection site is 1.5 mL. If more than 1.5 mL is required on a given dosing day, the total volume of burosumab-twza should be split and administered at two different injection sites. Monitor for signs of reactions.1

Visually inspect burosumab-twza for particulate matter and discoloration prior to administration. Burosumab-twza 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.1

Cautions for Burosumab-twza

Contraindications

  • Do not use burosumab-twza with oral phosphate and active vitamin D analogs.1

  • Do not initiate burosumab-twza if serum phosphorus is within or above the normal range for age.1

  • Burosumab-twza is contraindicated in patients with severe renal impairment or end stage renal disease.1

Warnings/Precautions

Hypersensitivity

Hypersensitivity reactions (e.g. rash, urticaria) have been reported in patients with burosumab-twza. Discontinue burosumab-twza if serious hypersensitivity reactions occur and initiate appropriate medical treatment.1

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 burosumab-twza, dose interruption and/or dose reduction may be required based on a patient’s serum phosphorus levels.1

Injection Site Reactions

Administration of burosumab-twza may result in local injection site reactions. Discontinue burosumab-twza if severe injection site reactions occur and administer appropriate medical treatment.1

Specific Populations

Pregnancy

Risk Summary: There are no available data on burosumab-twza 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 64-fold higher, by AUC, than the human exposure at 1 mg/kg every 4 weeks and were accompanied in the non-XLH monkeys by maternal hyperphosphatemia and placental mineralization. Serum phosphorus levels should be monitored throughout pregnancy. Report pregnancies to the Ultragenyx Adverse Event reporting line at 1-888-756-8657.1

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.1

Animal Data: In a reproductive toxicity study in pregnant cynomolgus monkeys without XLH, 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 1-, 7- and 64-fold human exposure at the adult human dose of 1 mg/kg every 4 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 64-fold the human exposure at the adult human dose of 1 mg/kg every 4 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 64-fold human exposure at the 1 mg/kg dose every 4 weeks. Burosumab-twza did not affect pre- and postnatal growth including survivability of the offspring.1

Lactation

There is no information regarding the presence of burosumab-twza in human milk, or the effects of burosumab-twza on milk production or the breastfed infant. Maternal IgG is present in breast milk. However, the effects of local gastrointestinal exposure and limited systemic exposure to burosumab-twza in the breastfed infant are unknown. The lack of clinical data during lactation precludes a clear determination of the risk of burosumab-twza to an infant during lactation. Therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for burosumab-twza and any potential adverse effects on the breastfed infant from burosumab-twza or from the underlying maternal condition.1

Pediatric Use

Safety and efficacy of burosumab-twza have been established in pediatric patients 1 year and older. Efficacy in pediatric patients 1 year and older with XLH is based on open label studies of 52 pediatric patients 5 to 12 years of age with XLH (Study 1), and in 13 pediatric patients 1 to 4 years of age with XLH (Study 2) evaluating serum phosphorus and radiographic findings. Efficacy in adolescents is supported by studies in pediatric patients less than 13 years of age. Dosing in this age group was derived using modeling and simulation of adult and pediatric PK and PD data.1

Safety and efficacy for burosumab-twza in pediatric patients with XLH below the age of 1 have not been established.1

Geriatric Use

Clinical studies of burosumab-twza did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.1

Common Adverse Effects

Most common adverse reactions (≥25%) in pediatric XLH patients are: headache, injection site reaction, vomiting, pyrexia, pain in extremity, vitamin D decreased.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 leg syndrome, vitamin D decreased, dizziness, constipation, blood phosphorus increased.1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Please see product labeling for drug interaction information.

Actions

Mechanism Of Action

X-linked hypophosphatemia is caused by excess fibroblast growth factor 23 (FGF23) which suppresses renal tubular phosphate reabsorption and the renal production of 1,25 dihydroxy vitamin D. Burosumab-twza binds to and inhibits the biological activity of FGF23, restoring renal phosphate reabsorption and increasing the serum concentration of 1,25 dihydroxy vitamin D.1

Advice to Patients

Hypersensitivity Reactions

Advise patients that burosumab-twza may cause hypersensitivity events such as rash, injection site rash and urticaria. Instruct the patients to contact their physician if such reactions occur.1

Injection Site Reactions

Inform patients that injection site reactions (e.g. erythema, rash, swelling, bruising, pain, pruritus, urticaria, and hematoma) have occurred at the site of burosumab-twza injection. Instruct the patients to contact their physician if such reactions occur.1

Restless Leg Syndrome

Advise patients that burosumab-twza can induce RLS or worsen the symptoms of existing RLS. Instruct the patients to contact their physician if such a reaction occurs.1

Pregnancy

Report pregnancies to the Ultragenyx Adverse Event reporting line at 1-888-756-8657.1

Additional Information

AHFSfirstRelease. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Burosumab-twza

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection

10 mg/1 mL

Crysvita

Ultragenyx Pharmaceutical Inc.

20 mg/1 mL

Crysvita

Ultragenyx Pharmaceutical Inc.

30 mg/1 mL

Crysvita

Ultragenyx Pharmaceutical Inc.

AHFS Drug Information. © Copyright 2019, Selected Revisions May 7, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Ultragenyx Pharmaceutical Inc.. CRYSVITA (Burosumab) SUBCUTANEOUS prescribing information. 2018 Apr. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6f5f3556-3197-477a-993c-96b2c29a91ac

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