Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Subcutaneous [preservative free]:
Crysvita: burosumab-twza 10 mg/mL (1 mL); burosumab-twza 20 mg/mL (1 mL); burosumab-twza 30 mg/mL (1 mL) [contains polysorbate 80]
Pharmacology
Mechanism of Action
Binds to and inhibits the activity of fibroblast growth factor 23 (FGF23), thereby restoring renal phosphate reabsorption and increasing the serum concentration of 1,25 dihydroxy vitamin D.
Pharmacokinetics/Pharmacodynamics
Distribution
Vd: 8 L
Metabolism
Degraded into small peptides and amino acids via catabolic pathways
Time to Peak
8 to 11 days
Half-Life Elimination
~19 days
Use in Specific Populations
Special Populations Note
Body weight: Clearance and volume of distribution of burosumab increases with body weight.
Use: Labeled Indications
X-linked hypophosphatemia: Treatment of X-linked hypophosphatemia in pediatric patients ≥6 months of age and adults.
Contraindications
Concomitant use with oral phosphate and/or active vitamin D analogs (eg, calcitriol, paricalcitol, doxercalciferol, calcifediol); serum phosphorus within or above normal range for age; severe renal impairment or end-stage renal disease.
Dosage and Administration
Dosing: Adult
Note: Prior to initiating burosumab, oral phosphate and active vitamin D analogs (eg, calcitriol, paricalcitol, doxercalciferol, calcifediol) should be discontinued for at least 1 week. Confirm baseline fasting serum phosphorus level is below the reference range for patient age before initiating burosumab.
Hypophosphatemia, X-linked: SubQ: Initial: 1 mg/kg every 4 weeks; calculated dose should be rounded to the nearest 10 mg; maximum dose: 90 mg.
Dosage adjustment based on serum phosphorus: Evaluate fasting serum phosphorus 2 weeks after treatment initiation and continue every 4 weeks for the first 12 weeks of therapy. Adjust dose accordingly based on fasting serum phosphorus level; see Reference Range for phosphorus age-based normal limits. Do not adjust dose more frequently than every 4 weeks.
If low serum phosphorus: There are no dosage adjustments provided in the manufacturer's labeling.
If normal serum phosphorus: Continue same dose.
If high serum phosphorus:
If fasting serum phosphorus above the normal age-based range, withhold next dose and reassess in 4 weeks; once serum phosphorus falls below the age-based normal range, may re-initiate burosumab at approximately one-half the initial starting dose up to a maximum dose of 40 mg every 4 weeks:
|
Re-Initiation Dosing |
|
|---|---|
|
Previous Dose (mg/dose) every 4 weeks |
Re-Initiation Dosea (mg/dose) every 4 weeks |
|
aRecheck fasting serum phosphorus 2 weeks after dose adjustment; based on results, determine if additional dosing adjustment necessary. |
|
|
40 |
20 |
|
50 |
20 |
|
60 |
30 |
|
70 |
30 |
|
≥80 |
40 |
Table has been converted to the following text:
Previous dose: 40 mg/dose every 4 weeks; Re-initiation dose: 20 mg/dose every 4 weeks
Previous dose: 50 mg/dose every 4 weeks; Re-initiation dose: 20 mg/dose every 4 weeks
Previous dose: 60 mg/dose every 4 weeks; Re-initiation dose: 30 mg/dose every 4 weeks
Previous dose: 70 mg/dose every 4 weeks; Re-initiation dose: 30 mg/dose every 4 weeks
Previous dose: ≥80 mg/dose every 4 weeks; Re-initiation dose: 40 mg/dose every 4 weeks
Missed dose: If a dose is missed, administer as soon as possible. To avoid missed doses, treatments may be administered 3 days on either side of the scheduled treatment date.
Dosing: Geriatric
Refer to adult dosing.
Dosing: Pediatric
Hypophosphatemia, X-linked (XLH): Note: Prior to initiating burosumab, oral phosphates and/or active vitamin D analogs (eg, calcitriol) should be discontinued for at least 1 week. Confirm that baseline fasting serum phosphorus concentration is below the reference range for patient age before initiating burosumab. During burosumab therapy, patients should have 25-hydroxy vitamin D levels monitored; supplement as necessary with cholecalciferol or ergocalciferol to maintain serum 25-hydroxy vitamin D levels in the normal range for age. Dose and interval are age-dependent; use extra precaution.
Initial:
Infants ≥6 months, Children, and Adolescents <18 years:
Weight <10 kg: SubQ: 1 mg/kg/dose every 2 weeks; calculated dose should be rounded to the nearest 1 mg.
Weight ≥10 kg: SubQ: 0.8 mg/kg/dose every 2 weeks; minimum dose: 10 mg/dose; calculated dose should be rounded to the nearest 10 mg; maximum dose: 90 mg/dose.
Adolescents ≥18 years: SubQ: 1 mg/kg/dose every 4 weeks; round dose to the nearest 10 mg; maximum dose: 90 mg/dose.
Monitoring of therapy: Evaluate fasting serum phosphorus every 4 weeks for first 12 weeks of therapy and as appropriate thereafter (eg, after dosing adjustments). Adjust dose accordingly based on fasting serum phosphorus level; see Reference Range for phosphorus age-based normal limits.
Dosing adjustment based on serum phosphorus:
If low serum phosphorus:
Infants ≥6 months, Children, and Adolescents <18 years: SubQ:
Weight <10 kg: If serum phosphorus below the reference range for age, increase dose to 1.5 mg/kg/dose every 2 weeks, rounded to the nearest 1 mg. Recheck fasting serum phosphorus 4 weeks after dose adjustment; burosumab should not be adjusted more frequently than every 4 weeks. If needed, dose may be further increased to the maximum dose of 2 mg/kg/dose.
Weight ≥10 kg: If serum phosphorus below the reference range for age, increase dose stepwise based on the following table. Recheck fasting serum phosphorus 4 weeks after dose adjustment; burosumab should not be adjusted more frequently than every 4 weeks. Maximum dose: 2 mg/kg/dose, not to exceed 90 mg/dose.
|
Weight-band (kg) |
Initial dose (mg/dose) every 2 weeks |
1st dose increase to mg/dose every 2 weeks |
2nd dose increase to mg/dose every 2 weeks |
|---|---|---|---|
|
A Presented doses already rounded B In trials, dose titration for every-2-week dosing was 0.2 mg/kg or 0.3 mg/kg (Carpenter 2018). |
|||
|
10 to 14 |
10 |
15 |
20 |
|
15 to 18 |
10 |
20 |
30 |
|
19 to 31 |
20 |
30 |
40 |
|
32 to 43 |
30 |
40 |
60 |
|
44 to 56 |
40 |
60 |
80 |
|
57 to 68 |
50 |
70 |
90 |
|
69 to 80 |
60 |
90 |
90 |
|
81 to 93 |
70 |
90 |
90 |
|
94 to 105 |
80 |
90 |
90 |
|
≥106 |
90 |
90 |
90 |
Table has been converted to the following text: Note: Presented doses already rounded.
Weight-band 10 to 14 kg:
Initial dose: 10 mg/dose every 2 weeks
1st dose increase: 15 mg/dose every 2 weeks
2nd dose increase: 20 mg/dose every 2 weeks
Weight-band 15 to 18 kg:
Initial dose: 10 mg/dose every 2 weeks
1st dose increase: 20 mg/dose every 2 weeks
2nd dose increase: 30 mg/dose every 2 weeks
Weight-band 19 to 31 kg:
Initial dose: 20 mg/dose every 2 weeks
1st dose increase: 30 mg/dose every 2 weeks
2nd dose increase: 40 mg/dose every 2 weeks
Weight-band 32 to 43 kg:
Initial dose: 30 mg/dose every 2 weeks
1st dose increase: 40 mg/dose every 2 weeks
2nd dose increase: 60 mg/dose every 2 weeks
Weight-band 44 to 56 kg:
Initial dose: 40 mg/dose every 2 weeks
1st dose increase: 60 mg/dose every 2 weeks
2nd dose increase: 80 mg/dose every 2 weeks
Weight-band 57 to 68 kg:
Initial dose: 50 mg/dose every 2 weeks
1st dose increase: 70 mg/dose every 2 weeks
2nd dose increase: 90 mg/dose every 2 weeks
Weight-band 69 to 80 kg:
Initial dose: 60 mg/dose every 2 weeks
1st dose increase: 90 mg/dose every 2 weeks
2nd dose increase: 90 mg/dose every 2 weeks
Weight-band 81 to 93 kg:
Initial dose: 70 mg/dose every 2 weeks
1st dose increase: 90 mg/dose every 2 weeks
2nd dose increase: 90 mg/dose every 2 weeks
Weight-band 94 to 105 kg:
Initial dose: 80 mg/dose every 2 weeks
1st dose increase: 90 mg/dose every 2 weeks
2nd dose increase: 90 mg/dose every 2 weeks
Weight-band ≥106 kg:
Initial dose: 90 mg/dose every 2 weeks
1st dose increase: 90 mg/dose every 2 weeks
2nd dose increase: 90 mg/dose every 2 weeks
Note: In trials, dose titration for every-2-week dosing was 0.2 mg/kg or 0.3 mg/kg (Carpenter 2018).
Adolescents ≥18 years: There are no dosage adjustments provided in the manufacturer's labeling for low serum phosphorus.
If normal serum phosphorus (ie, above the lower limit of reference range for age) and <5 mg/dL: Infants ≥6 months, Children, and Adolescents <18 years: Continue current dose; continue to monitor serum phosphorus as appropriate.
If high serum phosphorus:
Infants ≥6 months, Children, and Adolescents <18 years: If serum phosphorus >5 mg/dL: Hold next dose; reassess fasting serum phosphorus in 4 weeks and every 4 weeks thereafter; once serum phosphorus below reference range for age, may reinitiate burosumab at a reduced dose (see the following weight-directed re-initiation recommendations).
Re-initiation dosing: SubQ:
Patient weight <10 kg: Restart at 0.5 mg/kg/dose every 2 weeks; round dose to the nearest 1 mg. Recheck fasting serum phosphorus in 4 weeks and follow dosing adjustment recommendations based on result.
Patient weight ≥10 kg: See the following table. Recheck fasting serum phosphorus in 4 weeks and follow dosing adjustment recommendations based on result.
|
Previous dose (mg/dose) every 2 weeks |
Re-initiation dose (mg/dose) every 2 weeks |
|---|---|
|
10 |
5 |
|
15 |
10 |
|
20 |
10 |
|
30 |
10 |
|
40 |
20 |
|
50 |
20 |
|
60 |
30 |
|
70 |
30 |
|
80 |
40 |
|
90 |
40 |
Table has been converted to the following text:
Previous dose: 10 mg/dose every 2 weeks; Re-initiation dose: 5 mg/dose every 2 weeks
Previous dose: 15 mg/dose every 2 weeks; Re-initiation dose: 10 mg/dose every 2 weeks
Previous dose: 20 mg/dose every 2 weeks; Re-initiation dose: 10 mg/dose every 2 weeks
Previous dose: 30 mg/dose every 2 weeks; Re-initiation dose: 10 mg/dose every 2 weeks
Previous dose: 40 mg/dose every 2 weeks; Re-initiation dose: 20 mg/dose every 2 weeks
Previous dose: 50 mg/dose every 2 weeks; Re-initiation dose: 20 mg/dose every 2 weeks
Previous dose: 60 mg/dose every 2 weeks; Re-initiation dose: 30 mg/dose every 2 weeks
Previous dose: 70 mg/dose every 2 weeks; Re-initiation dose: 30 mg/dose every 2 weeks
Previous dose: 80 mg/dose every 2 weeks; Re-initiation dose: 40 mg/dose every 2 weeks
Previous dose: 90 mg/dose every 2 weeks; Re-initiation dose: 40 mg/dose every 2 weeks
Adolescents ≥18 years: If serum phosphorus above normal range: Hold next dose; reassess fasting serum phosphorus every 4 weeks; once serum phosphorus falls below the normal range, may reinitiate burosumab at a reduced dose (approximately half the initial starting dose; see the following table [maximum dose: 40 mg/dose]). Recheck fasting serum phosphorus 2 weeks after dose adjustment; based on results, determine if additional dosing adjustment necessary.
|
Previous dose (mg/dose) every 4 weeks |
Re-initiation dose (mg/dose) every 4 weeks |
|---|---|
|
40 |
20 |
|
50 |
20 |
|
60 |
30 |
|
70 |
30 |
|
≥80 |
40 |
Table has been converted to the following text:
Previous dose: 40 mg/dose every 4 weeks; Re-initiation dose: 20 mg/dose every 4 weeks
Previous dose: 50 mg/dose every 4 weeks; Re-initiation dose: 20 mg/dose every 4 weeks
Previous dose: 60 mg/dose every 4 weeks; Re-initiation dose: 30 mg/dose every 4 weeks
Previous dose: 70 mg/dose every 4 weeks; Re-initiation dose: 30 mg/dose every 4 weeks
Previous dose: ≥80 mg/dose every 4 weeks; Re-initiation dose: 40 mg/dose every 4 weeks
Administration
SubQ: Administer subcutaneously into the upper thighs, any quadrant of abdomen, buttocks, or upper arms. Contents from 2 vials may be combined; however, the maximum volume per injection site is 1.5 mL. Administer each injection at a different anatomic location than a previous injection and avoid areas where the skin is tender, bruised, red, hard, or not intact, or where there are scars or moles.
Storage
Store at 36°F to 46°F (2°C to 8°C) in the original carton; do not freeze. Protect from light. Do not shake.
Drug Interactions
Phosphate Supplements: May enhance the adverse/toxic effect of Burosumab. Exceptions: Sodium Glycerophosphate Pentahydrate. Avoid combination
Vitamin D Analogs: May enhance the adverse/toxic effect of Burosumab. Exceptions: Calcipotriene; Cholecalciferol; Ergocalciferol. Avoid combination
Adverse Reactions
>10%:
Central nervous system: Headache (children: 34% to 73%; adults: 13%), dizziness (10% to 15%), restless leg syndrome (adults: 12%)
Dermatologic: Skin rash (children: 10% to 27%)
Endocrine & metabolic: Vitamin D deficiency (children: 24% to 37%; adults: 12%)
Gastrointestinal: Vomiting (children: 41% to 48%), dental caries (children: 31%), diarrhea (children: 24%), toothache (children: 23%), constipation (9% to 17%), tooth infection (adults: 13%)
Infection: Tooth abscess (children: 15% to 34%)
Local: Injection site reaction (children: 52% to 67%)
Neuromuscular & skeletal: Limb pain (children: 38% to 46%), myalgia (children: 17%), back pain (adults: 15%)
Respiratory: Cough (children: 52%)
Miscellaneous: Fever (children: 44% to 55%)
1% to 10%:
Dermatologic: Rash at injection site (children: 6% to 10%), urticaria at injection site (children: 7%), urticaria (children: 5%)
Endocrine & metabolic: Hyperphosphatemia (adults: ≤7%)
Gastrointestinal: Nausea (children: 10%)
Hypersensitivity: Hypersensitivity reaction (6%)
Neuromuscular & skeletal: Muscle spasm (adults: 7%)
Warnings/Precautions
Concerns related to adverse effects:
- Hyperphosphatemia: Elevated serum phosphorus may increase the risk of nephrocalcinosis; dose reduction or interruption of therapy may be required.
- Hypersensitivity: May cause hypersensitivity reactions (eg, rash, urticaria). Discontinue therapy immediately if serious hypersensitivity reactions occur.
- Injection site reactions: Local injection site reactions may occur. Most reactions are mild in severity, occur within 1 day of injection, and typically resolve within 1 to 3 days with no treatment. Discontinue use if severe injection site reactions occur.
Disease-related concerns:
- Restless leg syndrome: New onset or worsening of existing restless leg syndrome has been reported in adults.
Other warnings/precautions:
- Vitamin D: May decrease serum vitamin D. Monitor serum 25(OH)D levels; supplement with cholecalciferol or ergocalciferol to maintain age-based normal range. Do NOT administer active vitamin D analogs during burosumab treatment.
Monitoring Parameters
Signs/symptoms of hypersensitivity or injection site reaction; serum 25-hydroxyvitamin D (25(OH)D) levels.
Serum phosphorus:
Children and Adolescents: Evaluate fasting serum phosphorus every 4 weeks for first 12 weeks of therapy and as appropriate thereafter (eg, after dosing adjustments).
Adults: Evaluate fasting serum phosphorus every 4 weeks, measured 2 weeks post-dose, for the first 12 weeks of treatment, and as appropriate thereafter (eg, after dosing adjustments).
Pregnancy
Pregnancy Considerations
Burosumab is a human IgG monoclonal antibody and may be transferred across the placenta. Maternal serum phosphorus concentrations should be monitored.
Health care providers are encouraged to report exposures of burosumab during pregnancy to the manufacturer Adverse Event reporting line (888-756-8657).
Patient Education
- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
- Patient may experience headache, vomiting, painful extremities, tooth pain, muscle pain, dizziness, or constipation. Have patient report immediately to prescriber signs of a kidney stone (back pain, abdominal pain, or blood in the urine), severe injection site irritation, or restless legs (HCAHPS).
- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.
