Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Kyowa Kirin Holdings B.V., Bloemlaan 2, 2132NP Hoofddorp, The Netherlands, +31 (0) 237200822, medinfo@kyowakirin.com
CRYSVITA is indicated for the treatment of X-linked hypophosphataemia, in children and adolescents aged 1 to 17 years with radiographic evidence of bone disease, and in adults.
CRYSVITA is indicated for the treatment of FGF23-related hypophosphataemia in tumour-induced osteomalacia associated with phosphaturic mesenchymal tumours that cannot be curatively resected or localised in children and adolescents aged 1 to 17 years and in adults.
Treatment should be initiated by a physician experienced in the management of patients with metabolic bone diseases.
Oral phosphate and active vitamin D analogues (e.g. calcitriol) should be discontinued 1 week prior to initiation of treatment. Vitamin D replacement or supplementation with inactive forms may be started or continued as per local guidelines under monitoring of serum calcium and phosphate. At initiation, fasting serum phosphate concentration should be below the reference range for age (see section 4.3).
The recommended starting dose in children and adolescents aged 1 to 17 years is 0.8 mg/kg of body weight given every two weeks. Doses should be rounded to the nearest 10 mg. The maximum dose is 90 mg.
After initiation of treatment with burosumab, fasting serum phosphate should be measured every 2 weeks for the first month of treatment, every 4 weeks for the following 2 months and thereafter as appropriate. Fasting serum phosphate should also be measured 2 weeks after any dose adjustment. If fasting serum phosphate is within the reference range for age, the same dose should be maintained.
Dose increase:
If fasting serum phosphate is below the reference range for age, the dose may be increased stepwise by 0.4 mg/kg up to a maximum dose of 2.0 mg/kg (maximum dose of 90 mg). Fasting serum phosphate should be measured 2 weeks after dose adjustment. Burosumab should not be adjusted more frequently than every 4 weeks.
Dose decrease:
If fasting serum phosphate is above the reference range for age, the next dose should be withheld and the fasting serum phosphate reassessed within 2 weeks. The patient must have fasting serum phosphate below the reference range for age to restart burosumab at half of the previous dose, rounding the amount as described above.
Dose Conversion at age 18 years:
Children and adolescents aged 1 to 17 years should be treated using the dosing guidance outlined above. At 18 years of age the patient should convert to the adult dose and dosing regimen as outlined below.
The recommended starting dose in adults is 1.0 mg/kg of body weight, rounded to the nearest 10 mg up to a maximum dose of 90 mg, given every 4 weeks.
After initiation of treatment with burosumab, fasting serum phosphate should be measured every 2 weeks for the first month of treatment, every 4 weeks for the following 2 months and thereafter as appropriate. Fasting serum phosphate should be measured 2 weeks after the previous dose of burosumab. If serum phosphate is within the normal range, the same dose should be continued.
Dose decrease:
If serum phosphate is above the upper limit of normal range, the next dose should be withheld and the serum phosphate level reassessed within 2 weeks. The patient must have serum phosphate below the normal range before restarting burosumab. Once serum phosphate is below the normal range, treatment may be restarted at half the initial starting dose up to a maximum dose of 40 mg every 4 weeks. Serum phosphate should be reassessed 2 weeks after any change in dose.
The posology in children and adolescents with TIO aged 1 to 17 years has been determined from pharmacokinetic modelling and simulation (see section 5.2).
The recommended starting dose for children aged 1 to 12 years is 0.4 mg/kg of body weight, given every 2 weeks. Doses should be rounded to the nearest 10 mg. The maximum dose is 90 mg.
Dose increase:
If serum phosphate is below the reference range for age, the dose may be increased in a stepwise manner. Doses should be increased by an initial increment of 0.6 mg/kg with subsequent increments, depending on patient’s response to treatment, of 0.5 mg/kg (up to a maximum dose of 2.0 mg/kg), rounding the amount as described above, up to a maximum dose of 90 mg, given every 2 weeks. Fasting serum phosphate should be measured 2 weeks after dose adjustment. Burosumab should not be adjusted more frequently than every 4 weeks.
The recommended starting dose for adolescents aged 13 to 17 years is 0.3 mg/kg of body weight, given every 2 weeks. Doses should be rounded to the nearest 10 mg. The maximum dose is 180 mg.
Dose increase:
If serum phosphate is below the reference range for age, the dose may be increased in a stepwise manner. Doses should be increased by an initial increment of 0.3 mg/kg with subsequent increments of between 0.2 mg/kg – 0.5 mg/kg (dose increment dependent on the patient’s serum phosphate response to treatment), rounding the amount as described above, up to a maximum dose of 2.0 mg/kg (maximum dose 180 mg), given every 2 weeks. Fasting serum phosphate should be measured 2 weeks after dose adjustment. Burosumab should not be adjusted more frequently than every 4 weeks.
For all paediatric patients, after initiation of treatment with burosumab, fasting serum phosphate should be measured every 2 weeks for the first month of treatment, every 4 weeks for the following 2 months and thereafter as appropriate. Fasting serum phosphate should also be measured 2 weeks after any dose adjustment. If fasting serum phosphate is within the reference range for age, the same dose should be maintained.
Dose decrease:
If serum phosphate is above the reference range for age, the next dose should be withheld and the fasting serum phosphate level reassessed in 2 weeks. Once serum phosphate is below the reference range for age, treatment may be restarted at half the previous dose in rounding the amount as described above. The fasting serum phosphate level should be assessed 2 weeks after the dose adjustment. If the level remains below the reference range for age after the re-started dose, the dose can be further adjusted.
Dose Conversion at age 18 years:
At 18 years of age the patient should convert to the adult dose and dosing regimen as outlined below.
The recommended starting dose for adults is 0.3 mg/kg body weight, rounded to the nearest 10 mg, given every 4 weeks.
After initiation of treatment with burosumab, fasting serum phosphate should be measured 2 weeks after each dose for the first 3 months of treatment, and thereafter as appropriate. If serum phosphate is within the reference range, the same dose should be maintained.
Dose increase:
If serum phosphate is below the reference range, the dose may be increased in a stepwise manner. Doses should be increased by an initial increment of 0.3 mg/kg, with subsequent increments of between 0.2 mg/kg – 0.5 mg/kg (dose dependent on the patient’s response to treatment), up to a maximum dose of 2.0 mg/kg (maximum dose 180 mg), given every 4 weeks. Fasting serum phosphate should be measured 2 weeks after dose adjustment.
For patients whose serum phosphate still remains below the reference range, despite providing the maximum dose every 4 weeks, the previous dose may be divided and given every 2 weeks, with incremental increases as required, as outlined above, up to a maximum dose of 2.0 mg/kg every 2 weeks (maximum dose 180 mg).
Dose decrease:
If serum phosphate is above the reference range, the next dose should be withheld and the fasting serum phosphate level reassessed in 2 weeks. The patient must have serum phosphate below the reference range before restarting burosumab. Once serum phosphate is below the reference range, treatment may be restarted at approximately half the previous dose, administered every 4 weeks. Serum phosphate should be reassessed 2 weeks after any change in dose.
If the level remains below the reference range after the re-started dose, the dose can be further adjusted.
If a patient undergoes treatment of the underlying tumour (i.e., surgical excision or radiation therapy) burosumab treatment should be interrupted.
Following completion of the treatment of the underlying tumour, serum phosphate should be reassessed before reinitiating treatment with burosumab. Burosumab treatment should be resumed at the patient’s original starting dose if serum phosphate level remains below the lower end of the normal reference range. Follow the recommended dose adjustment outlined above to maintain serum phosphate level within the normal reference range for age.
For all patients with TIO, treatment should be discontinued if the treating physician considers that no meaningful improvement in biochemical or clinical markers of response are observed, despite the maximum dose being administered.
To decrease the risk for ectopic mineralisation, it is recommended that fasting serum phosphate is targeted in the lower end of the normal reference range for age (see section 4.4).
Treatments may be administered 3 days either side of the scheduled treatment date if needed for practical reasons. If a patient misses a dose, burosumab should be resumed as soon as possible at the prescribed dose.
Burosumab has not been studied in patients with renal impairment. Burosumab must not be given to patients with severe or end stage renal disease (see section 4.3).
X-linked hypophosphataemia (XLH):
The safety and efficacy of burosumab in paediatric patients with XLH aged less than one year have not been established in clinical studies.
Tumour-induced osteomalacia (TIO):
The safety and efficacy of burosumab in paediatric patients with TIO have not been established in clinical studies.
Limited data is available in patients over 65 years of age.
For subcutaneous use.
Burosumab should be injected in the upper arm, abdomen, buttock or thigh.
The maximum volume of medicinal product per injection site is 1.5 ml. If more than 1.5 ml is required on a given dosing day, the total volume of medicinal product must be split and administered at two or more different injection sites. Injection sites should be rotated and carefully monitored for signs of potential reactions (see section 4.4).
For handling of burosumab before administration, see section 6.6.
For some patients, self/carer-administration with either the vial and/or the pre-filled syringe may be suitable. Once no immediate dose modifications are anticipated, the administration can be performed by an individual who has been trained properly in injection techniques. The first self-administered dose after drug initiation or dose change should be conducted under the supervision of a healthcare professional. Clinical monitoring of the patient, including monitoring of phosphate levels, must continue as required and as outlined below. A detailed ‘Instructions for Use’ section intended for the patient is provided at the end of the Package Leaflet.
There is no experience with overdose of burosumab. Burosumab has been administered in paediatric XLH clinical trials without dose limiting toxicity using doses up to 2.0 mg/kg body weight with a maximal dose of 90 mg every two weeks. In adult XLH clinical trials no dose limiting toxicity has been observed using doses up to 1.0 mg/kg or a maximal total dose of 128 mg every 4 weeks. In adult TIO clinical trials no dose limiting toxicity has been observed using doses up to 2.0 mg/kg or a maximal total dose of 184 mg every 4 weeks.
In case of overdose, it is recommended to stop burosumab and to monitor biochemical response.
3 years.
CRYSVITA solution for injection in pre-filled syringe:
Chemical and physical in-use stability has been demonstrated for 48 hours at 25°C when protected from light.
From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.
Store in a refrigerator (2°C to 8°C). Do not freeze.
Store in the original package in order to protect from light.
CRYSVITA solution for injection in vials:
Clear glass vial with butyl rubber stopper, and aluminium seal.
Pack size of one vial
CRYSVITA solution for injection in pre-filled syringe:
Clear type I glass syringe with a staked stainless steel needle. The syringe is closed by a rigid polypropylene and elastomer needle shield and a fluoropolymer-laminated bromobutyl rubber plunger stopper.
The different strengths of the medicinal product can be identified by a different coloured plunger rod: 10 mg (blue), 20 mg (red), and 30 mg (green).
Pack size of one pre-filled syringe.
CRYSVITA solution for injection in vials:
Each vial is for single use only.
Do not shake the vial before use.
Burosumab should be administered using aseptic technique and sterile disposable syringes and injection needles.
CRYSVITA solution for injection in pre-filled syringe:
Before administration, the solution should be inspected visually. The liquid should be clear to slightly opalescent, colourless to pale brown-yellow. If the solution is cloudy, discoloured or contains particles, the solution should not be used.
After removing the pre-filled syringe from the refrigerator, allow the syringe to reach room temperature for 45 minutes before injecting burosumab.
Comprehensive instructions for subcutaneous administration of burosumab in a pre-filled syringe is provided at the end of the package leaflet.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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