Posology : מינונים

3.      DOSAGE AND ADMINISTRATION

3.1 Important Dosage and Administration Information
Discontinue oral phosphate and/or active vitamin D analogs (e.g. calcitriol, paricalcitol, doxercalciferol, calcifediol) 1 week prior to initiation of treatment [see Contraindications (5)].
Fasting serum phosphorus concentration should be below the reference range for age prior to initiation of treatment [see Contraindications (5)].


CRYSVITA is administered by subcutaneous injection and should be administered by a healthcare provider.
The maximum volume of CRYSVITA per injection is 1.5 mL. If multiple injections are required, administer at different injection sites.
3.2 Pediatric Patients with X-linked Hypophosphatemia (6 months to less than 18 years of age) For patients who weigh less than 10 kg, the recommended starting dose is 1 mg/kg of body weight, rounded to the nearest 1 mg, administered every two weeks.
For patients who weigh 10 kg and greater, 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.
After initiation of treatment with CRYSVITA, 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.
Dose Adjustment
Reassess fasting serum phosphorus level 4 weeks after dose adjustment.
Do not adjust CRYSVITA more frequently than every 4 weeks.
Dose Increase:
For patients who weigh less than 10 kg, if serum phosphorus is below the reference range for age, the dose may be increased to 1.5 mg/kg, rounded to the nearest 1 mg, administered every two weeks. If additional dose increases are needed, the dose may be increased to the maximum dose of 2 mg/kg, rounded to the nearest 1 mg, administered every two weeks.
For patients who weigh 10 kg or greater, 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.
Table 1: XLH Pediatric Dose Schedule for Stepwise Dose Increase for Patients Weighing 10 kg or More
Body Weight (kg)      Starting Dose (mg)    First Dose Increase to   Second Dose Increase to (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                      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 CRYSVITA. Once serum phosphorus is below the reference range for age, treatment may be restarted.
For patients who weigh less than 10 kg, restart CRYSVITA at 0.5 mg/kg of body weight, rounded to the nearest 1 mg, administered every two weeks. For patients who weigh 10 kg or more, restart CRYSVITA according to the dose schedule shown in Table 2.
Table 2: XLH Pediatric Dose Schedule for Re-Initiation of Therapy for Patients Weighing 10 kg or More
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


After a dose decrease, reassess serum phosphorus level 4 weeks after the dose adjustment. If the level remains below the reference range for age after the re-initiation dose, the dose can be adjusted as outlined under Dose Increase.


3.3 Adult Patients with X-linked Hypophosphatemia (18 years of age and older) The recommended dose regimen in adults is 1 mg/kg body weight, rounded to the nearest 10 mg up to a maximum dose of 90 mg, administered every four weeks.
After initiation of treatment with CRYSVITA, 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.
Dose Decrease
Reassess fasting serum phosphorus level 2 weeks after dose adjustment.
Do not adjust CRYSVITA more frequently than every 4 weeks.
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 CRYSVITA. 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.
Table 3: XLH 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


3.4 Pediatric Patients with Tumor-induced Osteomalacia (2 years to less than 18 years of age) 
The recommended starting dose for pediatrics is 0.4 mg/kg body weight administered every 2 weeks, rounded to the nearest 10mg, up to a maximum dose of 2 mg/kg not to exceed 180mg, administered every 2 weeks.


After initiation of treatment with CRYSVITA, 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 reference range for age, continue with the same dose. Follow the dose adjustment schedule below to maintain serum phosphorus within the reference range for age.
Dose Adjustment
Reassess fasting serum phosphorus level 4 weeks after dose adjustment.
Do not adjust CRYSVITA more frequently than every 4 weeks.


Dose Increase
If serum phosphorus is below the reference range for age, the dose should be titrated in accordance with Table 4 up to the maximum dose of 2 mg/kg every 2 weeks. The maximum dose should not exceed 180 mg.
Table 4: TIO Pediatric Dose Schedule for Stepwise Dose Increase for Patients Weighing 10 kg or more
Body Weight      Starting Dose           First Dose         Second Dose          Third Dosea (kg)               (mg)              Increase to          Increase to         Increase to (mg)                (mg)                 (mg)
10 – 14              5                    10                   15                   20 15 – 18              5                    10                   20                   25 19 – 31             10                    20                   25                   30 32 – 43             10                    30                   40                   50        44 – 56             20                    40                   50                   70
57 – 68             20                    50                   70                   90 69 – 80             30                    60                   80                  100 81 – 93             30                    70                  100                  120 94 – 105             40                    80                  110                  140 106 and             40                    90                  130                  160 greater aThe table shows a dose increase up to 1.5 mg/kg. Further dose increases to a maximum of 2 mg/kg not to exceed 180 mg, administered every 2 weeks should be calculated by the physician.

Dose Decrease
If serum phosphorus is above the reference range for age, 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 CRYSVITA. Once serum phosphorus is below the reference range for age, treatment may be restarted at approximately half the initial starting dose, up to a maximum dose of 180 mg administered every 2 weeks for pediatrics. After a dose decrease, reassess serum 

phosphorus level 4 weeks after the dose adjustment. If the level remains below the reference range for age after the re-initiation dose, the dose can be adjusted as outlined per Table 4.
Dose Interruption
If a patient undergoes treatment of the underlying tumor (i.e., surgical excision or radiation therapy) CRYSVITA treatment should be interrupted and serum phosphorus reassessed after treatment has been completed. CRYSVITA dose should be restarted at the patient’s initiation dose if serum phosphorus remains below the lower limit of normal. Follow dose adjustment per Table 4 to maintain serum phosphorus within the reference range for age.
3.5 Adult Patients with Tumor-induced Osteomalacia (18 years of age and older) The recommended starting dose for adults is 0.5 mg/kg body weight administered every 4 weeks, rounded to the nearest 10 mg, up to a maximum dose of 2 mg/kg not to exceed 180mg, administered every 2 weeks.

After initiation of treatment with CRYSVITA, 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. Follow the dose adjustment schedule below to maintain serum phosphorus within the reference range.
Dose Adjustment
Reassess fasting serum phosphorus level 2 weeks after dose adjustment.
Do not adjust CRYSVITA more frequently than every 4 weeks.
Dose Increase
If serum phosphorus is below the normal range, the dose should be titrated in accordance with Table 5 up to the maximum dose of 2 mg/kg not to exceed 180 mg, administered every 2 weeks. For those individuals not reaching a serum phosphorus greater than the lower limit of the normal range, physicians may consider dividing total dose administered every 4 weeks and administering every 2 weeks.

Table 5: TIO Dose Schedule* for Stepwise** Dose Increase for Adults (18 years of age and older)
Starting Dose     First Dose    Second Dose      Third Dose     Fourth Dose        Fifth Dose Increase***     Increase***     Increase***     Increase           Increase (maximum dose)

If serum phosphorus        0.5 mg/kg      Increase to:    Increase to:    Increase to:    Increase to:     Increase to:     2 weeks       every 4 weeks post-dose                         1 mg/kg        1.5 mg/kg       2 mg/kg       1.5 mg/kg not   2 mg/kg not to adjustment                      every 4 weeks      every 4        every 4       to exceed 180   exceed 180 mg is below                                        weeks****      weeks****        mg every 2    every 2 weeks lower limit of                        OR                                             weeks normal                                            OR              OR
0.5 mg/kg every 2 weeks    0.75 mg/kg     1 mg/kg every every 2 weeks      2 weeks
*Rounded to the nearest 10 mg.

**Do not adjust CRYSVITA more frequently than every 4 weeks.

*** For those individuals not reaching a serum phosphorus greater than the lower limit of the normal range, physicians may consider dividing total dose administered every 4 weeks and administering every 2 weeks.

**** In patients with high body weight, if the calculated dose is greater than 180 mg every 4 weeks, move to a divided dose every 2 weeks.

Dose Decrease
If serum phosphorus is above the normal range, withhold the next dose and reassess the serum phosphorus level in 4 weeks. The patient must have serum phosphorus below the reference range to reinitiate CRYSVITA. Once serum phosphorus is below the reference range, treatment may be restarted at approximately half the initial starting dose, up to a maximum dose of 180 mg administered every 2 weeks for adults. After a dose decrease, reassess serum phosphorus level 2 weeks after the dose adjustment. If the level remains below the reference range after the re-initiation dose, the dose can be adjusted as outlined per Table 5.
Dose Interruption
If a patient undergoes treatment of the underlying tumor (i.e., surgical excision or radiation therapy) CRYSVITA treatment should be interrupted and serum phosphorus reassessed after treatment has been completed. CRYSVITA dose should be restarted at the patient’s initiation dose if serum phosphorus remains below the lower limit of normal. Follow dose adjustment per Table 5 to maintain serum phosphorus within the reference range.



3.6 Missed Dose
If a patient misses a dose, resume CRYSVITA as soon as possible at the prescribed dose. To avoid missed doses, treatments may be administered 3 days either side of the scheduled treatment date.
3.7 25-Hydroxy Vitamin D Supplementation
Monitor 25-hydroxy vitamin D levels. Supplement with cholecalciferol or ergocalciferol to maintain 25- hydroxy vitamin D levels in the normal range for age. Do not administer active Vitamin D analogs during CRYSVITA treatment [see Contraindications (5)].
3.8 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. If a given dose on a dosing day requires multiple vials of CRYSVITA, contents from two vials can be combined for injection. The maximum volume of CRYSVITA per injection is 1.5 mL. If multiple injections are required on a given dosing day, administer at different injection sites. Monitor for signs of reactions [see Warnings and Precautions (6.3)].
Visually inspect CRYSVITA for particulate matter and discoloration prior to administration. CRYSVITA 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.
4 DOSAGE FORMS AND STRENGTHS


Injection: 10mg/mL, 20 mg/mL, or 30 mg/mL clear to slightly opalescent and colorless to pale brown yellow solution in a single-dose vial.