2 DOSAGE AND ADMINISTRATION

2.1 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 [see Clinical Pharmacology (12.3)]. 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
* The recommended dosage for patients with a BSA less than 0.55 m2 has not been established.
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 m2	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 m2	35 mg twice daily
1.50 – 1.69 m2	40 mg twice daily
1.70 – 1.89 m2	45 mg twice daily
≥ 1.90 m2	50 mg twice daily

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.

2.2 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
* Permanently discontinue KOSELUGO in patients unable to tolerate KOSELUGO after two dose reductions.
Body Surface Area	First Dose Reduction (mg/dose)		Second Dose Reduction* (mg/dose)
Body Surface Area	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	25	10	10	10
1.10 – 1.29 m2	25	20	20	10
1.30 – 1.49 m2	25	25	25	10
1.50 – 1.69 m2	30	30	25	20
1.70 – 1.89 m2	35	30	25	20
≥ 1.90 m2	35	35	25	25

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 (5.1)]
• Asymptomatic decrease in left ventricular ejection fraction (LVEF) of 10% or greater from baseline and less than lower level of normal	Withhold until resolution. Resume at reduced dose.
• Symptomatic decreased LVEF • Grade 3 or 4 decreased LVEF	Permanently discontinue.
Ocular Toxicity [see Warnings and Precautions (5.2)]
• Retinal Pigment Epithelial Detachment (RPED)	Withhold until resolution. Resume at reduced dose.
• Retinal vein occlusion (RVO)	Permanently discontinue.
Gastrointestinal Toxicity[see Warnings and Precautions (5.3)]
• 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 (5.4)]
• Grade 3 or 4	Withhold until improvement. Resume at reduced dose.
Increased Creatine Phosphokinase (CPK) [see Warnings and Precautions (5.5)]
• Grade 4 Increased CPK • Any Increased CPK and myalgia	Withhold until improved to Grade 0 or 1. Resume at reduced dose. Permanently discontinue if no improvement within 3 weeks.
• Rhabdomyolysis	Permanently discontinue.
Other Adverse Reactions [see Adverse Reactions (6.1)]
• Intolerable Grade 2 • Grade 3	Withhold KOSELUGO until improved to Grade 0 or 1. Resume at 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

2.3 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 (8.7)].

Table 4 Recommended Dosage of KOSELUGO for Moderate Hepatic Impairment
Body Surface Area	Moderate Hepatic Impairment (Child-Pugh B) (mg/dose)
Body Surface Area	Morning	Evening
0.55 – 0.69 m2	10	10
0.70 – 0.89 m2	20	10
0.90 – 1.09 m2	20	20
1.10 – 1.29 m2	25	25
1.30 – 1.49 m2	30	25
1.50 – 1.69 m2	35	30
1.70 – 1.89 m2	35	35
≥ 1.90 m2	40	40

2.4 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 (7.1)].

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 twice daily, reduce to 20 mg/m2 twice daily (mg/dose)		If the current dosage is 20 mg/m2 twice daily, reduce to 15 mg/m2 twice daily (mg/dose)
Body Surface Area	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 m2	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 m2	35	35	30	25
≥ 1.90 m2	40	40	30	30