Posology : מינונים

4 DOSAGE AND ADMINISTRATION

4.1 Recommended Dosage
Initiate TAVALISSE at a dose of 100 mg taken orally twice daily. After a month, if platelet count has not increased to at least 50 × 109/L, increase TAVALISSE dose to 150 mg twice daily.
Use the lowest dose of TAVALISSE to achieve and maintain a platelet count at least 50 × 109/L as necessary to reduce the risk of bleeding.
TAVALISSE may be taken with or without food. In the case of a missed dose of TAVALISSE, instruct patients to take their next dose at its regularly scheduled time.

4.2 Monitoring
After obtaining baseline assessments:
Monitor CBCs, including platelet counts, monthly until a stable platelet count (at least 50 × 109/L) is achieved. Thereafter, continue to monitor CBCs, including neutrophils, regularly.
Monitor liver function tests (LFTs) (e.g., ALT, AST, and bilirubin) monthly.
Monitor blood pressure every 2 weeks until establishment of a stable dose, then monthly thereafter.

4.3 Dose Modification for Adverse Reactions
TAVALISSE dose modification is recommended based on individual safety and tolerability.
Management of some adverse reactions may require dose-interruption, reduction, or discontinuation.
A dose reduction schedule is provided in Table 1, based on daily dose. For example, if a patient is on the maximum dose at the time of an adverse reaction, the first dose reduction would be from 300 mg/day to 200 mg/day.

Table 1: Dose Reduction Schedule
Administered as:
Daily Dose                       AM                           PM
300 mg/day                    150 mg                       150 mg
200 mg/day                    100 mg                       100 mg
150 mg/day                     150 mg*                        ---
100 mg/day†                    100 mg*                        ---
* Once daily TAVALISSE should be taken in the morning.
† If further dose reduction below 100 mg/day is required, discontinue TAVALISSE.

The recommended dose modifications for adverse reactions are provided in Table 2.

Table 2: Recommended Dose Modifications and Management for
Specific Adverse Reactions
Adverse Reaction                         Recommended Action
Hypertension
Initiate or increase dosage of antihypertensive medication for patients with increased cardiovascular risk, and adjust as needed until
Stage 1: systolic between
BP is controlled.
130-139 or diastolic between 80-89 mmHg                If the BP target is not met after 8 weeks, reduce TAVALISSE to next lower daily dose
(refer to Table 1).

Initiate or increase dosage of antihypertensive medication, and adjust as needed until BP is controlled.
If BP remains 140/90 mmHg or higher for
Stage 2: systolic at least 140      more than 8 weeks, reduce TAVALISSE to or diastolic at least 90            next lower daily dose (refer to Table 1).
mmHg                                If BP remains 160/100 mmHg or higher for more than 4 weeks despite aggressive antihypertensive therapy, interrupt or discontinue TAVALISSE.

Interrupt or discontinue TAVALISSE.
Initiate or increase dosage of antihypertensive medication, and adjust as needed until BP is
Hypertensive crisis:                controlled. If BP returns to less than the target systolic over 180 and/or            BP, resume TAVALISSE at same daily dose.
diastolic over 120 mmHg             If repeat BP is 160/100 mmHg or higher for more than 4 weeks despite aggressive antihypertensive treatment, discontinue
TAVALISSE.

Hepatotoxicity
If patient is symptomatic (e.g., nausea, vomiting,
abdominal pain):
Interrupt TAVALISSE.
Recheck LFTs every 72 hours until ALT/AST values are no longer elevated (below 1.5 × ULN) and total BL remains less than 2 × ULN. Resume
TAVALISSE at next lower daily dose (refer to
Table 1).

If patient is asymptomatic:
AST/ALT is 3 × ULN or higher and less than 5 ×             Recheck LFTs every 72 hours until ALT/AST ULN                                  are below 1.5 × ULN) and total BL remains less than 2 × ULN.
Consider interruption or dose reduction of
TAVALISSE if ALT/AST and TBL remain in this category (AST/ALT is 3 to 5 × ULN; and total BL remains less than 2 × ULN)
If interrupted, resume TAVALISSE at next lower daily dose (refer to Table 1) when
ALT/AST are no longer elevated (below 1.5 ×
ULN) and total BL remains less than 2 × ULN.

Interrupt TAVALISSE. Recheck
LFTs every 72 hours:
If AST and ALT decrease, recheck until
ALT and AST are no longer elevated
AST/ALT is 5 × ULN or                   (below 1.5 × ULN) and total BL remains higher and total BL is less             less than 2 × ULN; resume TAVALISSE at than 2 × ULN                            next lower daily dose (refer to Table 1).
If AST/ALT persist at 5 × ULN or higher for 2 weeks or more, discontinue
TAVALISSE.
AST/ALT is 3 × ULN or
Discontinue TAVALISSE.
higher and total BL is greater than 2 × ULN
Continue TAVALISSE with frequent
Elevated unconjugated            monitoring since isolated increase in (indirect) BL in absence of      unconjugated (indirect) BL may be due to other LFT abnormalities          UGT1A1 inhibition

Diarrhea
Manage diarrhea using supportive measures
(e.g., dietary changes, hydration and/or antidiarrheal medication) early after the onset until symptom(s) have resolved.
Diarrhea                         If symptom(s) become severe (Grade 3 or above), temporarily interrupt TAVALISSE.
If diarrhea improves to mild (Grade 1), resume
TAVALISSE at the next lower daily dose (refer to Table 1).

Neutropenia
If absolute neutrophil count decreases (ANC less than 1.0 × 109/L) and remains low after 72 hours, temporarily interrupt TAVALISSE until
Neutropenia                      resolved (ANC greater than 1.5 × 109/L).
Resume TAVALISSE at the next lower daily dose (refer to Table 1).

ALT = alanine aminotransferase; AST = aspartate aminotransferase; BP = blood pressure; BL = bilirubin; ULN = upper limit of normal; LFT = liver function tests (AST, ALT, total BL with fractionation if elevated, alkaline phosphatase); AST/ALT = AST or ALT


4.4 Dose Modification for Drug Interactions
Concomitant use with a strong CYP3A4 inhibitor increases exposure to R406 (the major active metabolite).
Monitor for toxicities of TAVALISSE that may require TAVALISSE dose modifications (see Table 1) when given concurrently with a strong CYP3A4 inhibitor [see Drug Interactions (9.1)].

4.5 Discontinuation
Discontinue TAVALISSE after 12 weeks of treatment if the platelet count does not increase to a level sufficient to avoid clinically important bleeding [see Clinical Studies (14)].