Posology : מינונים

5          DOSAGE AND ADMINISTRATION
5.1
Select patients for the treatment of locally advanced or metastatic urothelial carcinoma with BALVERSA based on the presence of susceptible FGFR genetic alterations in tumor specimens [see Clinical Studies (14.1)].
5.2 Recommended Dosage and Schedule
The recommended starting dose of BALVERSA is 8 mg (two 4 mg tablets) orally once daily, with a dose increase to 9 mg (three 3 mg tablets) once daily based on serum 

phosphate (PO4) levels and tolerability at 14 to 21 days [see Dosage and Administration (5.3)].

Swallow tablets whole with or without food. If vomiting occurs any time after taking BALVERSA, the next dose should be taken the next day. Treatment should continue until disease progression or unacceptable toxicity occurs.

If a dose of BALVERSA is missed, it can be taken as soon as possible on the same day.
Resume the regular daily dose schedule for BALVERSA the next day. Extra tablets should not be taken to make up for the missed dose.

Dose Increase based on Serum Phosphate Levels

Assess serum phosphate levels 14 to 21 days after initiating treatment. Increase the dose of BALVERSA to 9 mg once daily if serum phosphate level is < 5.5 mg/dL and there are no ocular disorders or Grade 2 or greater adverse reactions. Monitor phosphate levels monthly for hyperphosphatemia [see Pharmacodynamics (12.2)].

5.3       Dose Modifications for Adverse Reactions
The recommended dose modifications for adverse reactions are listed in Table 1.

Table 1:            BALVERSA Dose Reduction Schedule
1st dose           2nd dose           3rd dose            4th dose             5th dose Dose reduction          reduction          reduction           reduction            reduction 9 mg                 8 mg               6 mg                5 mg                4 mg (three 3 mg          (two 4 mg          (two 3 mg           (one 5 mg           (one 4 mg              Stop tablets)             tablets)           tablets)            tablet)             tablet) 
8 mg                  6 mg               5 mg                4 mg
(two 4 mg            (two 3 mg          (one 5 mg           (one 4 mg              Stop tablets)              tablets)           tablet)             tablet)


Table 2 summarizes recommendations for dose interruption, reduction, or discontinuation of BALVERSA in the management of specific adverse reactions.

Table 2:    Dose Modifications for Adverse Reactions
Adverse Reaction            BALVERSA Dose Modification
Hyperphosphatemia
In all patients, restrict phosphate intake to 600-800 mg daily. If serum phosphate is above 7.0 mg/dL, consider adding an oral phosphate binder until serum phosphate level returns to < 5.5 mg/dL.
5.6-6.9 mg/dL (1.8-2.3               Continue BALVERSA at current dose.
mmol/L)
7.0-9.0 mg/dL (2.3-2.9               Withhold BALVERSA with weekly reassessments until level returns to mmol/L)                              < 5.5 mg/dL (or baseline). Then restart BALVERSA at the same dose level. A dose reduction may be implemented for hyperphosphatemia lasting > 1 week.


> 9.0 mg/dL (> 2.9 mmol/L)         Withhold BALVERSA with weekly reassessments until level returns to < 5.5 mg/dL (or baseline). Then may restart BALVERSA at 1 dose level lower.
> 10.0 mg/dL (> 3.2 mmol/L)        Withhold BALVERSA with weekly reassessments until level returns to or significant alteration in       < 5.5 mg/dL (or baseline). Then may restart BALVERSA at 2 dose baseline renal function or         levels lower.
Grade 3 hypercalcemia
Central Serous Retinopathy/Retinal Pigment Epithelial Detachment (CSR/RPED) Grade 1: Asymptomatic;        Withhold until resolution. If resolves within 4 weeks, resume at the clinical or diagnostic        next lower dose level. Then, if no recurrence for a month, consider re- observations only             escalation. If stable for 2 consecutive eye exams but not resolved, resume at the next lower dose level.
Grade 2: Visual acuity 20/40  Withhold until resolution. If resolves within 4 weeks, may resume at or better or ≤ 3 lines of     the next lower dose level.
decreased vision from baseline
Grade 3: Visual acuity worse  Withhold until resolution. If resolves within 4 weeks, may resume two than 20/40 or > 3 lines of    dose levels lower. If recurs, consider permanent discontinuation.
decreased vision from baseline
Grade 4: Visual acuity 20/200 Permanently discontinue.
or worse in affected eye
Other Adverse Reactions a
Grade 3                       Withhold BALVERSA until resolves to Grade 1 or baseline, then may resume dose level lower.
Grade 4                       Permanently discontinue.
a
Dose adjustment graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAEv4.03).

5.4 Pediatric Use
BALVERSA is not indicated for children and adolescents under 18 years old Safety and effectiveness of BALVERSA in pediatric patients have not been established.