Crysvita (burosumab-twza)

Burosumab dosage in adults should be adjusted no more frequently than every 4 weeks based on fasting serum phosphorus concentrations.

Following initiation of burosumab therapy, fasting serum phosphorus concentrations should be measured monthly (with determinations made 2 weeks after a dose) for the first 3 months, then as clinically appropriate thereafter. Fasting serum phosphorus concentrations should be measured 2 weeks after dosage adjustments.

If the serum phosphorus concentration is within the normal range, burosumab should be continued at the same dosage.

If the serum phosphorus concentration exceeds the normal range, the next dose of burosumab should be withheld and the serum phosphorus concentration assessed again in 4 weeks. Once the serum phosphorus concentration is less than the normal range, therapy with burosumab may be reinitiated at a reduced dose of approximately one-half the initial dose (not exceeding 40 mg). (See Table 1.)

Table 1. Burosumab-twza Dose Reduction in Adults.

Previous Dose (mg) Reduced Dose for Reinitiation (mg) 40 20 50 20 60 30 70 30 80 or greater 40

Burosumab dosage in pediatric patients should be adjusted no more frequently than every 4 weeks to maintain fasting serum phosphorus concentrations within the reference range for age.

Following initiation of burosumab therapy, fasting serum phosphorus concentrations should be measured every 4 weeks for the first 3 months, then as clinically appropriate thereafter. Fasting serum phosphorus concentrations should be measured 4 weeks after dosage adjustments.

If the serum phosphorus concentration exceeds the lower limit of the reference range for age but is below 5 mg/dL, burosumab should be continued at the same dosage.

If the serum phosphorus concentration is below the reference range for age, the dose may be increased in a stepwise manner, up to approximately 2 mg/kg (not exceeding 90 mg). (See Table 2.)

Table 2. Burosumab-twza Stepwise Dose Increases Based on Body Weight in Pediatric Patients 1 Year of Age or Older.

Body Weight (kg) Initial Dose (mg) Total Dose of Total Dose of First Stepwise Second Stepwise Dose Increase Dose Increase (mg) (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 or greater 90 Not applicable Not applicable

If the serum phosphorus concentration exceeds 5 mg/dL, the next dose of burosumab should be withheld and the serum phosphorus concentration assessed again in 4 weeks. Once the serum phosphorus concentration is less than the reference range for age, therapy with burosumab may be reinitiated at a reduced dose. (See Table 3.) The serum phosphorus concentration must be less than the reference range for age for reinitiation of the drug. If the concentration remains less than the reference range for age at 4 weeks after reinitiation at a reduced dose, the dosage can be increased. (See Table 2.)

Table 3. Burosumab-twza Dose Reduction in Pediatric Patients 1 Year of Age or Older.

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

Burosumab-twza is administered by subcutaneous injection. The drug should be administered by a clinician.

Burosumab-twza injection must be stored at 2-8degreesC and kept in the original carton for protection from light until time of use. Because burosumab-twza injection contains no preservatives, vials of the drug are intended for single dose only; unused portions remaining in the vial should be discarded.

Burosumab-twza injection should be inspected visually prior to administration. Burosumab-twza injection is a clear to slightly opalescent, colorless to pale brown-yellow solution. If the solution is discolored or cloudy or if any particles or foreign particulate matter is present, the drug must not be administered.

Subcutaneous injections should be made into the upper arms, upper thighs, buttocks, or any quadrant of the abdomen; injection sites should be rotated, with each injection administered at a different anatomic location than the previous injection. Injections should not be made into moles, scars, or areas where the skin is tender, bruised, erythematous, hard, or not intact.

No more than 1.5 mL of burosumab-twza solution should be injected subcutaneously at any one site; if the injection volume exceeds 1.5 mL, the total volume of the dose should be divided and administered at 2 separate injection sites.

If a dose of burosumab-twza is missed, the missed dose should be administered as soon as possible at the patient's usual dose.

No dosing information is available for this tab.

No dosing information is available for this tab.

Formal drug interaction studies have not been conducted with burosumab to date.

There are no contraindication interactions for this drug.

There are no severe interactions for this drug.

There are no moderate interactions for this drug.

Use of burosumab is contraindicated in combination with oral phosphate supplements and activated vitamin D analogs (e.g., calcitriol) and in patients with severe renal impairment or end-stage renal disease. The drug should not be initiated if serum phosphorus concentration is within or exceeds the normal range for age.

There are no contraindication contraindications for this drug.

There are no severe contraindications for this drug.

There are no moderate contraindications for this drug.

Adverse effects reported in more than 10% of pediatric patients receiving burosumab-twza in clinical studies include headache, injection site reaction, vomiting, pyrexia, pain in extremity, decreased vitamin D concentration, rash, toothache, myalgia, tooth abscess, and dizziness.

Adverse effects reported in more than 5% of adults receiving burosumab-twza in a clinical study and in at least 2 more burosumab-treated patients than placebo recipients include back pain, headache, tooth infection, new or worsening restless legs syndrome, decreased vitamin D concentration, dizziness, constipation, and hyperphosphatemia.

In phase 2 and 3 studies of burosumab-twza in adults with X-linked hypophosphatemia, 3.4% of patients underwent spinal surgery. Spinal stenosis is prevalent in adults with X-linked hypophosphatemia, and spinal cord compression also has been reported. Most cases requiring spinal surgery during these studies appeared to involve progression of preexisting spinal stenosis, but it is unknown whether burosumab exacerbates spinal stenosis or spinal cord compression.

There are no severe adverse reactions for this drug.

There are no less severe adverse reactions for this drug.

No enhanced messaging available.

Safety and efficacy of burosumab have not been established in pediatric patients younger than 1 year of age.

Safety and efficacy of burosumab have been 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. (See Rickets in Pediatric Patients under Uses: X-linked Hypophosphatemia.) Efficacy in adolescents with X-linked hypophosphatemia has been extrapolated from studies conducted in pediatric patients younger than 13 years of age, while dosage in adolescents was derived using modeling and simulation of both adult and pediatric pharmacokinetic and pharmacodynamic data.

No substantial age-related differences in the pharmacokinetics of burosumab have been observed.

Data regarding use of burosumab in pregnant women are lacking.

Burosumab crosses the placenta in monkeys. Reproduction studies in monkeys without X-linked hypophosphatemia have revealed no evidence of teratogenicity with IV burosumab-twza at exposure levels up to 64 times the exposure at the recommended adult dosage of 1 mg/kg every 4 weeks. Increases in late fetal loss and preterm births were observed but were not thought to indicate clinical risk since these effects were observed at the highest exposure and were accompanied by maternal hyperphosphatemia and placental mineralization. No adverse effects on prenatal and postnatal growth, including offspring survival, were observed.

If burosumab is used during pregnancy, serum phosphorus concentrations should be monitored throughout pregnancy. Pregnancies in patients receiving burosumab-twza should be reported to the Kyowa Kirin, Inc. Adverse Event reporting line at 888-756-8657.

It is not known whether burosumab is distributed into human milk. Effects of the drug on the breast-fed infant (e.g., resulting from local GI exposure or limited systemic exposure) or milk production also are not known. The benefits of breast-feeding and the woman's clinical need for burosumab should be considered along with any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.

The manufacturer makes no specific dosage recommendations for geriatric patients; in general, dosage selection should be cautious, usually initiating therapy at the low end of the usual range.

Clinical trials of burosumab did not include sufficient numbers of patients 65 years of age or older to determine whether geriatric patients respond differently than younger patients. While other clinical experience has not revealed age-related differences in response, dosage of burosumab generally should be selected carefully in geriatric patients, usually initiating therapy at the low end of the dosage range, because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly.

No substantial age-related differences in the pharmacokinetics of burosumab have been observed.