Dosage of Regorafenib

1.Recommended Dose

The recommended dose is 160 mg Regorafenib (four 40 mg tablets) taken orally once daily for the first 21 days of each28-day cycle. Continue treatment until disease progression or unacceptable
toxicity.

Take Regorafenib at the same time each day. Swallow tablet whole with water after a low-fat meal that contains less than600 calories and less than 30% fat [see Clinical Pharmacology (12.3)]. Do not
take two doses of Regorafenib on the same day to make up for a missed dose from the previous day.

2. Dose Modifications

If dose modifications are required, reduce the dose in 40 mg (one tablet) increments; the lowest recommended daily doseof Regorafenib is 80 mg daily.

Interrupt Regorafenib for the following:

• Grade 2 hand-foot skin reaction (HFSR) [palmar-plantar erythrodysesthesia syndrome (PPES)] that is recurrent or does not improve within 7 days despite dose reduction; interrupt therapy for a minimum of 7 days for Grade 3 HFSR

• Symptomatic Grade 2 hypertension

• Any Grade 3 or 4 adverse reaction

• Worsening infection of any grade

Reduce the dose of Regorafenib to 120 mg:

• For the first occurrence of Grade 2 HFSR of any duration

• After recovery of any Grade 3 or 4 adverse reaction except infection

• For Grade 3 aspartate aminotransferase (AST)/alanine aminotransferase (ALT)
elevation, only resume if the potential benefit outweighs the risk of hepatotoxicity

3. Reduce the dose of Regorafenib to 80 mg:

• For re-occurrence of Grade 2 HFSR at the 120 mg dose

• After recovery of any Grade 3 or 4 adverse reaction at the 120 mg dose (except hepatotoxicity or infection)

Discontinue Regorafenib permanently for the following:

• Failure to tolerate 80 mg dose

• Any occurrence of AST or ALT more than 20 times the upper limit of normal (ULN)

• Any occurrence of AST or ALT more than 3 times ULN with concurrent bilirubin more than 2 times ULN

• Re-occurrence of AST or ALT more than 5 times ULN despite dose reduction to 120 mg

• For any Grade 4 adverse reaction; only resume if the potential benefit outweighs the risks

from FDA，2020.02