Posology : מינונים

2          DOSAGE AND ADMINISTRATION

2.1        Patient Selection
Select patients for treatment with GAVRETO based on the presence of a RET gene fusion (NSCLC or thyroid cancer) or RET gene mutation (MTC) [see Clinical Studies (14)].

2.2        Recommended Dosage
The recommended dosage of GAVRETO is 400 mg orally once daily on an empty stomach (the capsules should be swallowed whole with a glass of water, no food intake for at least 2 hours before and at least 1 hour after taking GAVRETO) [see Clinical Pharmacology (12.3)].
Continue treatment until disease progression or until unacceptable toxicity.
If a dose of GAVRETO is missed, it can be taken as soon as possible on the same day. Resume the regular daily dose schedule for GAVRETO the next day.
Do not take an additional dose if vomiting occurs after GAVRETO but continue with the next dose as scheduled.

2.3        Dosage Modifications for Adverse Reactions
The recommended dose reductions and dosage modifications for adverse reactions are provided in Table 1 and Table 2.
Table 1:           Recommended Dose Reductions for GAVRETO for Adverse Reactions Dose Reduction                           Recommended Dosage
First                                    300 mg once daily
Second                                   200 mg once daily
Third                                    100 mg once daily


Permanently discontinue GAVRETO in patients who are unable to tolerate 100 mg taken orally once daily.
The recommended dosage modifications for adverse reactions are provided in Table 2.

Table 2:           Recommended Dosage Modifications for GAVRETO for Adverse Reactions Adverse Reaction                     Severity*                            Dosage Modification ILD/Pneumonitis                      Grade 1 or 2                         Withhold GAVRETO until [see Warnings and Precautions                                             resolution. Resume by reducing (5.1)]                                                                    the dose as shown in Table 1.
Permanently discontinue
GAVRETO for recurrent
ILD/pneumonitis.
Grade 3 or 4                         Permanently discontinue for confirmed ILD/pneumonitis.

Hypertension                         Grade 3                              Withhold GAVRETO for Grade 3 hypertension that persists
[see Warnings and Precautions                                             despite optimal antihypertensive (5.2)]                                                                    therapy. Resume at a reduced dose when hypertension is controlled.
Grade 4                              Discontinue GAVRETO.

Hepatotoxicity [see Warnings         Grade 3 or 4                         Withhold GAVRETO and monitor AST/ALT once weekly and Precautions (5.3)] until resolution to Grade 1 or baseline.
Resume at reduced dose (Table
1).
For recurrent events at Grade 3 or higher, discontinue
GAVRETO.

Hemorrhagic Events                   Grade 3 or 4                         Withhold GAVRETO until recovery to baseline or Grade 0
[see Warnings and Precautions                                             or 1.
(5.4)]                                                                    Discontinue GAVRETO for severe or life-threatening hemorrhagic events.
Other Adverse Reactions              Grade 3 or 4                         Withhold GAVRETO until [see Adverse Reactions (6.1)]                                             improvement to ≤ Grade 2.
Resume at reduced dose (Table
1).
Permanently discontinue for recurrent Grade 4 adverse reactions.
* Adverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03

2.4          Dose Modification for Use with Combined P-glycoprotein (P-gp) and
Strong CYP3A Inhibitors
Avoid coadministration of GAVRETO with known combined P-gp and strong CYP3A inhibitors. If coadministration with a combined P-gp and strong CYP3A inhibitor cannot be avoided, reduce the current dose of GAVRETO as recommended in Table 3. After the inhibitor has been discontinued for 3 to 5 elimination half-lives, resume GAVRETO at the dose taken prior to initiating the combined P-gp and strong CYP3A inhibitor [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].
Table 3:           Recommended Dosage Modifications for GAVRETO for Coadministration with Combined P-gp and Strong CYP3A Inhibitors
Current GAVRETO                                         Recommended GAVRETO Dosage Dosage
400 mg orally once daily                                             200 mg orally once daily

300 mg orally once daily                                              200 mg orally once daily 
200 mg orally once daily                                              100 mg orally once daily


2.5          Dose Modification for Use with Strong CYP3A Inducers
Avoid coadministration of GAVRETO with strong CYP3A inducers. If coadministration with a strong CYP3A inducer cannot be avoided, increase the starting dose of GAVRETO to double the current GAVRETO dosage starting on Day 7 of coadministration of GAVRETO with the strong CYP3A inducer. After the inducer has been discontinued for at least 14 days, resume GAVRETO at the dose taken prior to initiating the strong CYP3A inducer [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].