Posology : מינונים

2     DOSAGE AND ADMINISTRATION

2.1   Patient Selection
Select patients for treatment with RETEVMO based on the presence of a RET gene fusion (NSCLC thyroid cancer, or other solid tumors) or specific RET gene mutation (MTC) in tumor specimens [see Clinical Studies (14)].

2.2   Important Administration Instructions
RETEVMO may be taken with or without food unless coadministered with a proton pump inhibitor (PPI) [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].

2.3   Recommended Dosage
The recommended dosage of RETEVMO based on body weight is:
•   Less than 50 kg: 120 mg
•   50 kg or greater: 160 mg
Take RETEVMO orally twice daily (approximately every 12 hours) until disease progression or unacceptable toxicity.

Swallow the capsules whole. Do not crush or chew the capsules.
Do not take a missed dose unless it is more than 6 hours until next scheduled dose.
If vomiting occurs after RETEVMO administration, do not take an additional dose and continue to the next scheduled time for the next dose.

2.4      Dosage Modifications for Concomitant Use of Acid-Reducing Agents
Avoid concomitant use of a PPI, a histamine-2 (H2) receptor antagonist, or a locally-acting antacid with RETEVMO [see Drug Interactions (7.1)]. If concomitant use cannot be avoided: •   Take RETEVMO with food when coadministered with a PPI.
•   Take RETEVMO 2 hours before or 10 hours after administration of an H2 receptor antagonist.
•   Take RETEVMO 2 hours before or 2 hours after administration of a locally-acting antacid.

2.5      Dosage Modifications for Adverse Reactions
The recommended dose reductions for adverse reactions are provided in Table 1.

Table 1: Recommended RETEVMO Dose Reductions for Adverse Reactions
Patients Weighing                        Patients Weighing
Dose Reduction                          Less Than 50 kg                          50 kg or Greater First                                80 mg orally twice daily                 120 mg orally twice daily Second                               40 mg orally twice daily                 80 mg orally twice daily Third                                40 mg orally once daily                  40 mg orally twice daily 

Permanently discontinue RETEVMO in patients unable to tolerate three dose reductions.
The recommended dosage modifications for adverse reactions are provided in Table 2.
Table 2: Recommended RETEVMO Dosage Modifications for Adverse Reactions Adverse              Severity                               Dosage Modification Reaction
Hepatotoxicity       Grade 3    •   Withhold RETEVMO and monitor AST/ALT once weekly until resolution to [see Warnings        or             Grade 1 or baseline.
and Precautions      Grade 4    •   Resume at reduced dose by 2 dose levels and monitor AST and ALT once (5.1)]                              weekly until 4 weeks after reaching dose taken prior to the onset of Grade 3 or 4 increased AST or ALT.
•   Increase dose by 1 dose level after a minimum of 2 weeks without recurrence and then increase to dose taken prior to the onset of Grade 3 or 4 increased AST or ALT after a minimum of 4 weeks without recurrence.
Interstitial Lung    Grade 2    •   Withhold RETEVMO until resolution.
Disease/                        •   Resume at a reduced dose.
Pneumonitis                     •   Discontinue RETEVMO for recurrent ILD/pneumonitis.
[see Warnings
Grade 3    •   Discontinue RETEVMO for confirmed ILD/pneumonitis.
and Precautions or
(5.2)]
Grade 4


Hypertension       Grade 3    •   Withhold RETEVMO for Grade 3 hypertension that persists despite [see Warnings                     optimal antihypertensive therapy. Resume at a reduced dose when and Precautions                   hypertension is controlled.
(5.3)]             Grade 4    •   Discontinue RETEVMO.
QT Interval        Grade 3    •   Withhold RETEVMO until recovery to baseline or Grade 0 or 1.
Prolongation                  •   Resume at a reduced dose.
[see Warnings      Grade 4    •   Discontinue RETEVMO.
and Precautions
(5.4)]
Hemorrhagic        Grade 3    •   Withhold RETEVMO until recovery to baseline or Grade 0 or 1.
Events             or         •   Discontinue RETEVMO for severe or life-threatening hemorrhagic events.
[see Warnings      Grade 4 and Precautions
(5.5)]
Hypersensitivity   All        •   Withhold RETEVMO until resolution of the event. Initiate corticosteroids.
Reactions          Grades     •   Resume at a reduced dose by 3 dose levels while continuing [see Warnings                     corticosteroids.
and Precautions               •   Increase dose by 1 dose level each week until the dose taken prior to the (5.6)]                            onset of hypersensitivity is reached, then taper corticosteroids.
Hypothyroidism     Grade 3    •   Withhold RETEVMO until resolution to Grade 1 or baseline.
[see Warnings      or         •   Discontinue RETEVMO based on severity.
and Precautions    Grade 4
(5.9)]
Other Adverse      Grade 3    •   Withhold RETEVMO until recovery to baseline or Grade 0 or 1.
Reactions          or         •   Resume at a reduced dose.
[see Adverse       Grade 4
Reactions (6.1)]

2.6     Dosage Modifications for Concomitant Use of Strong and Moderate CYP3A Inhibitors
Avoid concomitant use of strong and moderate CYP3A inhibitors with RETEVMO. If concomitant use of a strong or moderate CYP3A inhibitor cannot be avoided, reduce the RETEVMO dose as recommended in Table 3. After the inhibitor has been discontinued for 3 to 5 elimination half-lives, resume RETEVMO at the dose taken prior to initiating the CYP3A inhibitor [see Drug Interactions (7.1)].

Table 3: Recommended RETEVMO Dosage for Concomitant Use of Strong and Moderate CYP3A Inhibitors
Recommended RETEVMO Dosage
Current RETEVMO Dosage                  Moderate CYP3A Inhibitor               Strong CYP3A Inhibitor 120 mg orally twice daily                  80 mg orally twice daily             40 mg orally twice daily 160 mg orally twice daily                 120 mg orally twice daily             80 mg orally twice daily 
2.7     Dosage Modification for Severe Hepatic Impairment
Reduce the recommended dosage of RETEVMO for patients with severe hepatic impairment as recommended in Table 4 [see Use in Specific Populations (8.7)].



Table 4: Recommended RETEVMO Dosage for Severe Hepatic Impairment
Current RETEVMO Dosage                                            Recommended RETEVMO Dosage 120 mg orally twice daily                                                 80 mg orally twice daily 160 mg orally twice daily                                                 80 mg orally twice daily