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Burosumab-twza

Class: Electrolytic, Caloric, and Water Balance Agents; Miscellaneous
Chemical Name: Disulfide with human monoclonal KRN23 light chain, anti-(human fibroblast growth factor 23) (human monoclonal KRN23 heavy chain), immunoglobulin G1 dimer
Molecular Formula: C6388H9904N1700O2006S46
CAS Number: 1610833-03-8
Brands: Crysvita

Medically reviewed by Drugs.com. Last updated on Jun 17, 2019.

Introduction

Recombinant fully human IgG1 monoclonal antibody to human fibroblast growth factor 23 (FGF23), a bone-derived hormone that regulates phosphate and vitamin D homeostasis.1 3 4 6 9

Uses for Burosumab-twza

X-linked Hypophosphatemia

Management of X-linked hypophosphatemia (previously known as familial vitamin D-resistant rickets) (designated an orphan drug by FDA for use in this condition).1 2 3 4 8 12

Improves serum phosphorus concentrations and reduces osteomalacia-related bone lesions (e.g., bone histomorphometric parameters, active fractures) in adults.1 4 8

Improves serum phosphorus concentrations and radiographic measures of rickets severity in pediatric patients.1 3 8 12

Burosumab-twza Dosage and Administration

General

  • Discontinue oral phosphate supplements and activated vitamin D analogs (e.g., calcitriol) 1 week prior to initiation of burosumab.1

  • Initiate burosumab therapy only if fasting serum phosphorus concentration is less than reference range for age; manufacturer states that drug initiation is contraindicated if serum phosphorus is within or exceeds normal range for age.1

Restricted Distribution

Available only from a limited network of specialty pharmacies.14 15 Contact manufacturer for additional information.

Administration

Sub-Q Administration

A clinician should administer the drug.1

Burosumab-twza injection is a clear to slightly opalescent, colorless to pale brown-yellow solution.1 Discard if solution is discolored or cloudy or if any particles or foreign particulate matter is present.1

Inject sub-Q into upper arms, upper thighs, buttocks, or any quadrant of the abdomen; rotate sites.1 Do not inject into moles, scars, or areas where the skin is tender, bruised, erythematous, hard, or not intact.1

If total volume of dose >1.5 mL, divide and administer at 2 separate injection sites; do not administer >1.5 mL at any 1 site.1

If a dose is missed, administer missed dose as soon as possible.1

Dosage

Pediatric Patients

X-linked Hypophosphatemia
Initial Dosage
Sub-Q

Pediatric patients 1 to <18 years of age: 0.8 mg/kg every 2 weeks.1 Round dose to nearest 10 mg (minimum initial dose 10 mg).1 Do not exceed 90 mg.1

Dosage Titration
Sub-Q

Adjust dosage no more frequently than every 4 weeks to maintain fasting serum phosphorus concentrations within reference range for age.1

Measure fasting serum phosphorus concentrations every 4 weeks for the first 3 months of therapy, then as clinically appropriate thereafter.1 Measure fasting serum phosphorus concentrations 4 weeks after dosage adjustments.1

If serum phosphorus concentration is greater than lower limit of reference range for age but <5 mg/dL, continue same dosage.1

If serum phosphorus concentration is less than reference range for age, may increase dose in a stepwise manner, up to approximately 2 mg/kg (not exceeding 90 mg).1 (See Table 1.)

Table 1. Burosumab-twza Stepwise Dose Increases Based on Body Weight in Pediatric Patients ≥1 Year of Age.1

Body Weight (kg)

Initial Dose (mg)

Total Dose of First Stepwise Dose Increase (mg)

Total Dose of Second Stepwise Dose Increase (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

Not applicable

81–93

70

90

Not applicable

94–105

80

90

Not applicable

≥106

90

Not applicable

Not applicable

If serum phosphorus concentration is >5 mg/dL, withhold next dose and reassess serum phosphorus concentration in 4 weeks.1 Once concentration is less than reference range for age, reinitiate therapy at a reduced dose.1 (See Table 2.) Serum phosphorus concentration must be less than reference range for age for reinitiation of drug.1 If the concentration remains less than reference range for age at 4 weeks after reinitiation at reduced dose, dosage can be increased.1 (See Table 1.)

Table 2. Burosumab-twza Dose Reduction in Pediatric Patients ≥1 Year of Age.1

Previous Dose (mg)

Reduced Dose for Reinitiation (mg)

10

5

15

10

20

10

30

10

40

20

50

20

60

30

70

30

80

40

90

40

Adults

X-linked Hypophosphatemia
Initial Dosage
Sub-Q

1 mg/kg every 4 weeks.1 Round dose to nearest 10 mg.1 Do not exceed 90 mg.1

Dosage Titration
Sub-Q

Adjust dosage no more frequently than every 4 weeks based on fasting serum phosphorus concentrations.1

Measure fasting serum phosphorus concentrations monthly (2 weeks after a dose) for first 3 months of therapy, then as clinically appropriate thereafter.1 Measure fasting serum phosphorus concentrations 2 weeks after dosage adjustments.1

If serum phosphorus concentration is within normal range, continue same dosage.1

If serum phosphorus concentration exceeds normal range, withhold next dose and reassess serum phosphorus concentration in 4 weeks.1 Once serum phosphorus concentration is less than normal range, reinitiate therapy at reduced dose of approximately one-half the initial dose (not exceeding 40 mg).1 (See Table 3.)

Table 3. Burosumab-twza Dose Reduction in Adults.1

Previous Dose (mg)

Reduced Dose for Reinitiation (mg)

40

20

50

20

60

30

70

30

≥80

40

Prescribing Limits

Pediatric Patients

X-linked Hypophosphatemia
Sub-Q

Minimum initial dose: 10 mg.1 Maximum dose: 90 mg.1

Adults

X-linked Hypophosphatemia
Sub-Q

Maximum 90 mg.1

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.1

Renal Impairment

Severe renal impairment or end-stage renal disease: Use contraindicated because of abnormal bone metabolism.1

Mild or moderate renal impairment: No specific dosage recommendations at this time.1

Geriatric Patients

No specific dosage recommendations; in general, select dosage cautiously, initiating therapy at low end of usual range.1

Cautions for Burosumab-twza

Contraindications

  • Concomitant use with oral phosphate supplements and activated vitamin D analogs (e.g., calcitriol).1 8

  • Initiation of drug if serum phosphorus is within or exceeds normal range for age.1

  • Severe renal impairment or end-stage renal disease.1

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity Reactions

Hypersensitivity reactions (e.g., rash, urticaria) reported.1 3 4 12 Generally mild or moderate and did not require drug discontinuance.1 4

Discontinue burosumab if serious hypersensitivity reactions occur, and initiate appropriate medical treatment.1

Hyperphosphatemia and Risk of Nephrocalcinosis

Increases in serum phosphorus concentrations exceeding ULN may be associated with increased risk of nephrocalcinosis.1

Treatment interruption and subsequent dosage reduction may be necessary if hyperphosphatemia occurs.1 (See Dosage under Dosage and Administration.)

Injection Site Reactions

Injection site reactions (e.g., urticaria, erythema, rash, swelling, bruising, pain, pruritus, hematoma) reported.1 Reactions generally were mild, occurred ≤1 day after injection, lasted 1–3 days, required no treatment, and resolved in nearly all cases.1

Monitor for injection site reactions.1 Discontinue burosumab if severe injection site reactions occur, and initiate appropriate medical treatment.1

Immunogenicity

Preexisting antiburosumab antibodies detected in some patients.1 Antiburosumab antibodies not detected in patients who were antibody negative at baseline;1 4 however, the incidence of antibody formation may be underestimated since burosumab-twza can interfere with the assay.1 Clinical relevance of antiburosumab antibodies unknown.1

Specific Populations

Pregnancy

No data regarding use in pregnant women.1

Crosses the placenta in monkeys.1 No evidence of teratogenicity or adverse effects on prenatal and postnatal growth, including offspring survival, in monkeys; increases in late fetal loss and preterm births not thought to indicate clinical risk since effects occurred at highest exposure level and were accompanied by maternal hyperphosphatemia and placental mineralization.1

If used during pregnancy, monitor serum phosphorus concentrations throughout pregnancy.1 Report pregnancies in patients receiving burosumab-twza to Kyowa Kirin, Inc. Adverse Event reporting line at 888-756-8657.1

Lactation

Not known whether burosumab distributes into milk, affects the breast-fed infant (e.g., via local GI exposure or limited systemic exposure), or affects milk production.1 Consider benefits of breast-feeding and woman’s clinical need for the drug along with any potential adverse effects on breast-fed infant from the drug or underlying maternal condition.1

Pediatric Use

Safety and efficacy not established in pediatric patients <1 year of age.1

Safety and efficacy established in 2 open-label studies in 52 children 5–12 years of age and 13 children 1–4 years of age with X-linked hypophosphatemia.1 3 12 Efficacy in adolescents supported by studies in children <13 years of age; adolescent dosage derived using modeling and simulation of adult and pediatric pharmacokinetic/pharmacodynamic data.1

No clinically important age-related differences in pharmacokinetics.1 9

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger patients.1 Select dosage cautiously.1

No clinically important age-related differences in pharmacokinetics.1

Hepatic Impairment

Effect of hepatic impairment on pharmacokinetics unknown.1

Renal Impairment

Contraindicated in patients with severe renal impairment or end-stage renal disease because of abnormal mineral metabolism.1

Effect of renal impairment on pharmacokinetics unknown.1

Common Adverse Effects

Pediatric patients: Headache,1 3 12 injection site reaction,1 3 12 vomiting,1 3 12 pyrexia,1 3 12 pain in extremity,1 3 12 decreased vitamin D concentration,1 rash,1 3 toothache,1 12 myalgia,1 3 tooth abscess,1 12 dizziness.1

Adults: Back pain,1 4 headache,1 4 tooth infection,1 new or worsening restless legs syndrome,1 4 decreased vitamin D concentration,1 dizziness,1 4 constipation,1 hyperphosphatemia.1 4 Some patients required spinal surgery, generally for progression of preexisting spinal stenosis; unknown whether burosumab exacerbates spinal stenosis or spinal cord compression in adults with X-linked hypophosphatemia.1

Interactions for Burosumab-twza

No formal drug interaction studies to date.1

Specific Drugs

Drug

Interaction

Comments

Phosphate supplements, oral

Risk of hyperphosphatemia8

Concomitant use contraindicated;1 discontinue oral phosphate supplements 1 week before initiating burosumab1

Vitamin D analogs, activated (e.g., calcitriol)

Risk of hyperphosphatemia8

Concomitant use contraindicated;1 discontinue activated vitamin D analogs 1 week before initiating burosumab1

Burosumab-twza Pharmacokinetics

Absorption

Bioavailability

Following sub-Q injection, absolute bioavailability nearly 100%.7 10

Exhibits linear pharmacokinetics within the dosage range of 0.1–1 mg/kg.1

Mean time to peak plasma concentrations is 8–11 days.1 10

Duration

Duration of action is longer with sub-Q injection than with IV administration.10

Distribution

Extent

Not known whether distributed into human milk.1

Special Populations

Volume of distribution increases with body weight.1

Elimination

Metabolism

Exact pathway not characterized; however, expected to be degraded into small peptides and amino acids.1 Hepatic mechanisms unlikely to be involved.9

Half-life

Absorption half-life following sub-Q injection: Approximately 2 days.7

Elimination half-life: Approximately 13–19 days.1 7 10

Special Populations

Clearance increases with body weight.1

Age does not substantially affect pharmacokinetics.1 9

Stability

Storage

Parenteral

Injection

2–8°C.1 Store in original carton to protect from light until use.1 Do not freeze or shake.1

Actions

  • Binds to the bone-derived hormone FGF23, which regulates phosphate homeostasis, controlling reabsorption of phosphate in the kidney, and also regulates expression of 1α-hydroxylase, the rate-limiting enzyme in renal activation of vitamin D.1 3 4 6

  • In X-linked hypophosphatemia, loss-of-function mutations in the phosphate-regulating endopeptidase homolog X-linked (PHEX) gene lead to excess FGF23 and resultant suppression of renal tubular phosphate reabsorption and renal synthesis of 1,25-dihydroxyvitamin D, renal phosphate wasting, and impaired bone mineralization.1 3 4 6 9

  • Burosumab binds at the N-terminal domain to both intact FGF23 and FGF23 polypeptide fragments, restoring renal phosphate reabsorption and increasing serum concentrations of 1,25-dihydroxyvitamin D.1 10 11

  • Magnitude and duration of response are dose related.9 10 11 Renal tubular phosphate reabsorption, serum phosphorus concentrations, and 1,25-dihydroxyvitamin D concentrations increase linearly with increasing drug exposure.1 7 11 Increases in serum phosphorus concentrations return to baseline with drug elimination.1

  • Elevations in serum total FGF23 observed after drug initiation;1 7 clinical implication is unknown,1 but some researchers suggest this could indicate a need for higher doses with long-term therapy.7

Advice to Patients

  • Risk of hypersensitivity reactions.1 Importance of patients contacting their clinician if such reactions (e.g., rash, injection site rash, urticaria) occur.1

  • Risk of injection site reactions.1 Importance of patients contacting their clinician if such reactions (e.g., erythema, rash, swelling, bruising, pain, pruritus, urticaria, hematoma) occur.1

  • Risk of new-onset or worsening restless legs syndrome.1 Importance of patients contacting their clinician if such a reaction occurs.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Importance of reporting pregnancies to the manufacturer's adverse event reporting line at 888-756-8657.1 (See Pregnancy under Cautions.)

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

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.

Distribution is restricted.14 15 (See Restricted Distribution under Dosage and Administration.)

Burosumab-twza

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, for subcutaneous use

10 mg/mL

Crysvita

Ultragenyx

20 mg/mL

Crysvita

Ultragenyx

30 mg/mL

Crysvita

Ultragenyx

AHFS DI Essentials™. © Copyright 2019, Selected Revisions June 17, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Ultragenyx Pharmaceutical Inc. Crysvita (burosumab-twza) injection prescribing information. Novato, CA; 2018 Sep.

2. Food and Drug Administration. FDA Application: Search Orphan Drug Designations and Approvals. Silver Spring, MD. From FDA website. Accessed 2018 Nov 20. https://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm

3. Carpenter TO, Whyte MP, Imel EA et al. Burosumab Therapy in Children with X-Linked Hypophosphatemia. N Engl J Med. 2018; 378:1987-1998. http://www.ncbi.nlm.nih.gov/pubmed/29791829?dopt=AbstractPlus

4. Insogna KL, Briot K, Imel EA et al. A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial Evaluating the Efficacy of Burosumab, an Anti-FGF23 Antibody, in Adults With X-Linked Hypophosphatemia: Week 24 Primary Analysis. J Bone Miner Res. 2018; 33:1383-1393. http://www.ncbi.nlm.nih.gov/pubmed/29947083?dopt=AbstractPlus

5. Burosumab. Drugs and Lactation Database (LactMed) [Internet]. Bethesda (MD): National Library of Medicine (US); 2006-. Updated 2018 Oct 1. Accessed 2018 Nov 20.

6. Erben RG, Andrukhova O. FGF23-Klotho signaling axis in the kidney. Bone. 2017; 100:62-68. http://www.ncbi.nlm.nih.gov/pubmed/27622885?dopt=AbstractPlus

7. Zhang X, Peyret T, Gosselin NH et al. Population pharmacokinetic and pharmacodynamic analyses from a 4-month intradose escalation and its subsequent 12-month dose titration studies for a human monoclonal anti-FGF23 antibody (KRN23) in adults with X-linked hypophosphatemia. J Clin Pharmacol. 2016; 56:429-38. http://www.ncbi.nlm.nih.gov/pubmed/26247790?dopt=AbstractPlus

8. Food and Drug Administration. Center for Drug Evaluation and Research. Application number: 761068Orig1s000: Multi-discipline review. From FDA website. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/761068Orig1s000MultidisciplineR.pdf

9. Lamb YN. Burosumab: First Global Approval. Drugs. 2018; 78:707-714. http://www.ncbi.nlm.nih.gov/pubmed/29679282?dopt=AbstractPlus

10. Carpenter TO, Imel EA, Ruppe MD et al. Randomized trial of the anti-FGF23 antibody KRN23 in X-linked hypophosphatemia. J Clin Invest. 2014; 124:1587-97. http://www.ncbi.nlm.nih.gov/pubmed/24569459?dopt=AbstractPlus

11. Zhang X, Imel EA, Ruppe MD et al. Pharmacokinetics and pharmacodynamics of a human monoclonal anti-FGF23 antibody (KRN23) in the first multiple ascending-dose trial treating adults with X-linked hypophosphatemia. J Clin Pharmacol. 2016; 56:176-85. http://www.ncbi.nlm.nih.gov/pubmed/26073451?dopt=AbstractPlus

12. Whyte MP, Carpenter TO, Gottesman GS et al. Efficacy and safety of burosumab in children aged 1-4 years with X-linked hypophosphataemia: a multicentre, open-label, phase 2 trial. Lancet Diabetes Endocrinol. 2019; 7:189-199. http://www.ncbi.nlm.nih.gov/pubmed/30638856?dopt=AbstractPlus

13. Imel EA, White KE. Pharmacological management of X-linked hypophosphataemia. Br J Clin Pharmacol. 2018; http://www.ncbi.nlm.nih.gov/pubmed/30207609?dopt=AbstractPlus

14. Ultragenyx Pharmaceutical Inc. Ultragenyx and Kyowa Kirin announce Crysvita (burosumab-twza) now launched in the U.S. for the treatment of X-linked hypophosphatemia (XLH) in children and adults. Novato, CA; 2018 Apr 30. Press release. http://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-and-kyowa-kirin-announce-crysvitar-burosumab-twza-now

15. PANTHERx Specialty Pharmacy. PANTHERx Specialty Pharmacy selected by Ultragenyx to distribute Crysvita. Pittsburgh, PA; 2018 Jun 7. Press release. https://www.prnewswire.com/news-releases/pantherx-specialty-pharmacy-selected-by-ultragenyx-to-distribute-crysvita-300661361.html

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