Posology : מינונים

5         DOSAGE AND ADMINISTRATION
5.1       Recommended Dosage
The recommended dosage of KOSELUGO is 25 mg/m2 orally twice daily (approximately every 12 hours) until disease progression or unacceptable toxicity.
Koselugo can be taken with or without food The recommended dose of KOSELUGO based on body surface area (BSA) is shown in Table 1.
Table 1           Recommended Dosage Based on Body Surface Area
Body Surface Area*                                 Recommended Dosage 0.55 – 0.69 m2                     20 mg in the morning and 10 mg in the evening 0.70 – 0.89 m    2
20 mg twice daily
0.90 – 1.09 m2                                    25 mg twice daily 1.10 – 1.29 m2                                    30 mg twice daily 1.30 – 1.49 m    2
35 mg twice daily
1.50 – 1.69 m2                                    40 mg twice daily 1.70 – 1.89 m2                                    45 mg twice daily ≥ 1.90 m   2
50 mg twice daily
*   The recommended dosage for patients with a BSA less than 0.55m2 has not been established.
Swallow KOSELUGO capsules whole with water. Do not chew, dissolve or open capsule.
Do not administer to patients who are unable to swallow a whole capsule.
Do not take a missed dose of KOSELUGO unless it is more than 6 hours until the next scheduled dose.
If vomiting occurs after KOSELUGO administration, do not take an additional dose, but continue with the next scheduled dose.

For opening and closing of the bottle, press the cap and turn simultaneously.
5.2       Dosage Modifications for Adverse Reactions
The recommended dose reductions for adverse reactions are provided in Table 2.
Table 2          Recommended Dose Reductions for KOSELUGO for Adverse Reactions 
Body Surface Area                  First Dose Reduction               Second Dose Reduction* (mg/dose)                            (mg/dose)
Morning               Evening        Morning               Evening
0.55 – 0.69 m2                  10                   10                   10 once daily 0.70 – 0.89 m   2
20                   10              10                   10
0.90 – 1.09 m2                  25                   10              10                   10 1.10 – 1.29 m   2
25                   20              20                   10
1.30 – 1.49 m   2
25                   25              25                   10
1.50 – 1.69 m2                  30                   30              25                   20 1.70 – 1.89 m   2
35                   30              25                   20
≥ 1.90 m2                    35                   35              25                   25 * Permanently   discontinue KOSELUGO in patients unable to tolerate KOSELUGO after two dose reductions.

Dosage modifications for adverse reactions are in Table 3.
Table 3            Recommended Dosage Modifications for KOSELUGO for Adverse Reactions Severity of Adverse Reaction           Recommended Dosage Modifications for KOSELUGO Cardiomyopathy [see Warnings and Precautions (8.1)]
• Asymptomatic decrease in left        Withhold until resolution. Resume at reduced dose.
ventricular ejection fraction
(LVEF) of10% or greater from baseline and less than lower level of normal
• Symptomatic decreased LVEF           Permanently discontinue.
• Grade 3 or 4 decreased LVEF
Ocular Toxicity [see Warnings and Precautions (8.2)]
• Retinal Pigment Epithelial           Withhold until resolution. Resume at reduced dose.
Detachment (RPED)
• Retinal vein occlusion (RVO)         Permanently discontinue.
Gastrointestinal Toxicity [see Warnings and Precautions (8.3)]
• Grade 3 Diarrhea                     Withhold until improved to Grade 0 or 1. Resume at same dose.
Permanently discontinue if no improvement within 3 days.
• Grade 4 Diarrhea                     Permanently discontinue.
• Grade 3 or 4 Colitis                 Permanently discontinue.
Skin Toxicity [see Warnings and Precautions (8.4)]
• Grade 3 or 4                         Withhold until improvement. Resume at reduced dose.
Increased Creatine Phosphokinase (CPK) [see Warnings and Precautions (8.5)] 
Severity of Adverse Reaction          Recommended Dosage Modifications for KOSELUGO • Grade 4 Increased CPK               Withhold until improved to Grade 0 or 1. Resume at reduced dose.
Permanently discontinue if no improvement within 3 weeks.
• Any Increased CPK and myalgia
• Rhabdomyolysis                      Permanently discontinue.
Other Adverse Reactions [see Adverse Reactions (9)]
• Intolerable Grade 2                 Withhold KOSELUGO until improved to Grade 0 or 1. Resume at • Grade 3                             reduced dose.

• Grade 4                             Withhold KOSELUGO until improved to Grade 0 or 1. Resume at reduced dose. Consider discontinuation.
* Per National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 
5.3     Dosage Modifications for Hepatic Impairment
Reduce the recommended dosage of KOSELUGO to 20 mg/m2 orally twice daily in patients with moderate hepatic impairment (Child-Pugh B). The recommended dosage of KOSELUGO for use in patients with severe hepatic impairment (Child-Pugh C) has not been established [see Use in Specific Populations (11)].
Table 4          Recommended Dosage of KOSELUGO for Moderate Hepatic Impairment Body Surface Area                               Moderate Hepatic Impairment (Child-Pugh B)
(mg/dose)
Morning                           Evening
0.55 – 0.69 m   2
10                               10
0.70 – 0.89 m2                            20                               10 0.90 – 1.09 m   2
20                               20
1.10 – 1.29 m2                            25                               25 1.30 – 1.49 m   2
30                               25
1.50 – 1.69 m2                            35                               30 1.70 – 1.89 m   2
35                               35
≥ 1.90 m2                               40                               40 
5.4     Dosage Modifications for Drug Interactions
Strong or Moderate CYP3A4 Inhibitors or Fluconazole
Avoid coadministration of strong or moderate CYP3A4 inhibitors or fluconazole with KOSELUGO. If coadministration with strong or moderate CYP3A4 inhibitors or fluconazole cannot be avoided, reduce the KOSELUGO dosage as recommended in Table 5. After discontinuation of the strong or moderate 


CYP3A4 inhibitor or fluconazole for 3 elimination half-lives, resume the KOSELUGO dose that was taken prior to initiating the inhibitor or fluconazole [see Drug Interactions (10)].
Table 5             Recommended Dosage of KOSELUGO for Coadministration with Strong or Moderate CYP3A4 Inhibitors or Fluconazole
Body Surface Area          If the current dosage is 25 mg/m2      If the current dosage is 20 mg/m2 twice daily, reduce to 20 mg/m 2 twice    twice daily, reduce to 15 mg/m 2 daily                               twice daily
(mg/dose)                                (mg/dose)

Morning               Evening           Morning                Evening 0.55 – 0.69 m2             10                     10                    10 mg once daily 0.70 – 0.89 m2             20                     10               10                      10 0.90 – 1.09 m2             20                     20               20                      10 1.10 – 1.29 m    2
25                     25               25                      10
1.30 – 1.49 m2             30                     25               25                      20 1.50 – 1.69 m2             35                     30               25                      25 1.70 – 1.89 m    2
35                     35               30                      25
≥ 1.90 m   2
40                     40               30                      30

6          DOSAGE FORMS AND STRENGTHS
Capsules:
•    10 mg: white to off-white, hard capsule, banded and marked with “SEL 10” in black ink.
•    25 mg: blue, hard capsule, banded and marked with “SEL 25” in black ink.