Usual Adult Dose for Colorectal Cancer

160 mg orally once a day for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity

Uses:

• Metastatic colorectal cancer (CRC) previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and an anti-EGFR therapy if RAS wild-type
• Locally advanced, unresectable or metastatic GI stromal tumor (GIST) previously treated with imatinib mesylate and sunitinib malate
• Hepatocellular carcinoma (HCC) previously treated with sorafenib

Usual Adult Dose for Gastrointestinal Stromal Tumor

160 mg orally once a day for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity

Uses:

• Metastatic colorectal cancer (CRC) previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and an anti-EGFR therapy if RAS wild-type
• Locally advanced, unresectable or metastatic GI stromal tumor (GIST) previously treated with imatinib mesylate and sunitinib malate
• Hepatocellular carcinoma (HCC) previously treated with sorafenib

Usual Adult Dose for Hepatocellular Carcinoma

160 mg orally once a day for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity

Uses:

• Metastatic colorectal cancer (CRC) previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and an anti-EGFR therapy if RAS wild-type
• Locally advanced, unresectable or metastatic GI stromal tumor (GIST) previously treated with imatinib mesylate and sunitinib malate
• Hepatocellular carcinoma (HCC) previously treated with sorafenib

Renal Dose Adjustments

No adjustment recommended.

Liver Dose Adjustments

Mild (Child-Pugh A) hepatic impairment: No adjustment recommended.
Moderate (Child-Pugh B) hepatic impairment: Dose adjustment(s) may be required; however, no specific guidelines have been suggested. Caution recommended.
Severe (Child-Pugh C) hepatic impairment: Not recommended.

DOSE MODIFICATIONS FOR HEPATIC IMPAIRMENT:
ALT AND/OR AST:
GREATER than or equal to 5 times upper limit of normal (ULN) (maximum Grade 2):

• Any occurrence: Continue therapy; monitor liver function weekly until transaminases return to less than 3 x ULN (Grade 1) or baseline

• First occurrence: Interrupt therapy; monitor transaminases weekly until return to less than 3 times ULN or baseline.
• Restart: If the potential benefit outweighs the risk of hepatotoxicity, restart therapy, reduce dose by 40 mg, and monitor liver function weekly for at least 4 weeks
• Reoccurrence: Permanently discontinue therapy.

• Any occurrence: Permanently discontinue therapy.

• Any occurrence: Permanently discontinue therapy; Monitor liver function weekly until resolution or return to baseline.
• Exception: Patients with Gilbert's syndrome who develop elevated transaminases should be managed as per the above outlined recommendations for the respective observed elevation of ALT and/or AST.

Dose Adjustments

If dose modifications are required, reduce the dose in 40 mg increments; the lowest recommended daily dose is 80 mg daily.

INTERRUPT DOSING FOR:

• Grade 2 hand-foot skin reaction (HFSR; palmar-plantar erythrodysesthesia syndrome) that is recurrent or does not improve within 7 days despite dose reduction; interrupt dosing for at least 7 days for Grade 3 HFSR.
• Symptomatic Grade 2 hypertension
• Any Grade 3 or 4 adverse reaction
• Worsening infection of any Grade

• First occurrence of Grade 2 HFSR of any duration
• After recovery of any Grade 3 or 4 adverse reaction (except infection)

• Recurrence 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)

• Failure to tolerate 80 mg dose
• Any Grade 4 adverse reaction; only resume therapy if the potential benefit outweighs the risks

Precautions

US BOXED WARNINGS:
HEPATOTOXICITY:

• Severe, sometimes fatal, hepatotoxicity has been reported.

• Monitor hepatic function prior to and during therapy.
• Interrupt and then reduce the dose or discontinue this drug for hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis, depending upon severity and persistence.

• None

Dialysis

Data not available

Other Comments

Administration advice:

• Take this drug at the same time each day.
• Swallow tablet whole with water after a low-fat meal that contains less than 600 calories and less than 30% fat.
• Do not take 2 doses of this drug on the same day to make up for a missed dose from the previous day.

• Store at 25C (77F); excursions are permitted from 15C to 30C (59F to 86).
• To protect from moisture, keep tablets in the original bottle and do not remove the desiccant.
• Keep the bottle tightly closed after opening; discard any unused tablets 7 weeks after opening the bottle.

• The manufacturer product information should be consulted.

• Overdose: There is no known antidote; in the event of suspected overdose: immediately interrupt dosing, institute supportive care, and observe until clinical stabilization.

• Cardiovascular: Blood pressure (weekly for the first 6 weeks of therapy and then every cycle or more frequently, as clinically indicated)
• Hepatic: ALT, AST, bilirubin (at least every 2 weeks during the first 2 months of therapy; thereafter, monitor monthly or more frequently as clinically indicated)
• Metabolism: Biochemical and metabolic parameters (periodically during treatment)

• Avoid drinking grapefruit juice and taking St. John's Wort during treatment.
• Take this drug after eating a low-fat meal that contains less than 30% fat and less than 600 calories. An example: 1 cup of cereal (about 30 g), 1 glass (about 250 mL) of skim milk, 1 slice of toast with jam, 1 glass of apple juice, and 1 cup of coffee or tea (2 g fat, 520 calories).