Usual Adult Dose for Non-Small Cell Lung Cancer

Less than 50 kg: 120 mg orally 2 times daily (approximately every 12 hours) until disease progression or unacceptable toxicity

50 kg or greater: 160 mg orally 2 times daily (approximately every 12 hours) until disease progression or unacceptable toxicity

Use: For the treatment of adult patients with metastatic RET fusion-positive non-small cell lung cancer (NSCLC)

Usual Adult Dose for Thyroid Cancer

Less than 50 kg: 120 mg orally 2 times daily (approximately every 12 hours) until disease progression or unacceptable toxicity

50 kg or greater: 160 mg orally 2 times daily (approximately every 12 hours) until disease progression or unacceptable toxicity

Uses:

• For the treatment of adult patients with advanced or metastatic RET-mutant medullary thyroid cancer (MTC) who require systemic therapy.
• For the treatment of adult patients with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate)

Usual Pediatric Dose for Thyroid Cancer

12 years and older:
Less than 50 kg: 120 mg orally 2 times daily (approximately every 12 hours) until disease progression or unacceptable toxicity

12 years and older:
50 kg or greater: 160 mg orally 2 times daily (approximately every 12 hours) until disease progression or unacceptable toxicity

Uses:

• For the treatment of pediatric patients 12 years and older with advanced or metastatic RET-mutant medullary thyroid cancer (MTC) who require systemic therapy
• For the treatment of pediatric patients 12 years and older with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate)

Renal Dose Adjustments

Mild to moderate renal impairment (CrCl greater than 30 mL/min): No adjustment recommended.
Severe renal impairment (CrCl less than 30 mL/min or end-stage renal disease): Data not available

Liver Dose Adjustments

Mild (total bilirubin less than or equal to ULN with AST greater than upper limit of normal [ULN] or total bilirubin greater than 1 to 1.5 times ULN with any AST) or moderate (total bilirubin greater than 1.5 to 3 x ULN and any AST): No adjustment recommended.
Severe (total bilirubin greater than 3 to 10 x ULN and any AST) hepatic impairment:

• Current dose of this drug is 120 mg orally 2 times daily: Reduce dose to 80 mg orally 2 times daily.
• Current dose of this drug is 160 mg orally 2 times daily: Reduce dose to 80 mg orally 2 times daily.

Dose Adjustments

RECOMMENDED DOSE REDUCTIONS FOR ADVERSE REACTIONS:
First dose reduction:

• Less than 50 kg: 80 mg orally 2 times daily
• Fifty (50) kg or greater: 120 mg orally 2 times daily

• Less than 50 kg: 40 mg orally 2 times daily
• Fifty (50) kg or greater: 80 mg orally 2 times daily

• Less than 50 kg: 40 mg orally 2 times daily
• Fifty (50) kg or greater: 40 mg orally 2 times daily

• Grade 3 or 4: Withhold therapy and monitor AST/ALT once weekly until resolution to Grade 1 or baseline.
• Resume therapy at reduced dose by 2 dose levels and monitor AST and ALT once weekly until 4 weeks after reaching dose taken prior to the onset of Grade 3 or 4 increased AST or ALT.
• Increase dose by 1 dose level after a minimum of 2 weeks without recurrence and then increase to dose taken prior to the onset of Grade 3 or 4 increased AST or ALT after a minimum of 4 weeks without recurrence.

• Grade 3: Withhold therapy for Grade 3 hypertension that persists despite optimal antihypertensive therapy; resume at a reduced dose when hypertension is controlled.
• Grade 4: Discontinue this drug.

• Grade 3: Withhold therapy until recovery to baseline or Grade 0 or 1; resume at a reduced dose.
• Grade 4: Discontinue this drug.

• Grade 3 or 4: Withhold therapy until recovery to baseline or Grade 0 or 1; discontinue therapy for severe or life-threatening hemorrhagic events.

• All grades: Withhold therapy until resolution of the event; initiate corticosteroids; resume at a reduced dose by 3 dose levels while continuing corticosteroids; increase dose by 1 dose level each week until the dose taken prior to the onset of hypersensitivity is reached, then taper corticosteroids.

• Grade 3 or 4: Withhold therapy until recovery to baseline or Grade 0 or 1; resume therapy at a reduced dose.

• Avoid concomitant use of strong and moderate CYP450 3A inhibitors with this drug.
• If concomitant use of a strong or moderate CYP450 3A inhibitor cannot be avoided, reduce the dose of this drug as recommended.
• After the inhibitor has been discontinued for 3 to 5 elimination half-lives, resume this drug at the dose taken prior to initiating the CYP450 3A inhibitor.

• Moderate CYP450 3A inhibitor: Reduce dose to 80 mg orally 2 times daily.
• Strong CYP450 3A inhibitor: Reduce dose to 40 mg orally 2 times daily.

• Moderate CYP450 3A inhibitor: Reduce dose to 120 mg orally 2 times daily.
• Strong CYP450 3A inhibitor: Reduce dose to 80 mg orally 2 times daily.

Precautions

CONTRAINDICATIONS:

• None

Dialysis

Data not available

Other Comments

Administration advice:

• This drug may be taken with or without food unless coadministered with a proton pump inhibitor (PPI); take with food if given with a PPI, a histamine-2 (H2) receptor antagonist, or a locally acting antacid. If concomitant use cannot be avoided, take this drug with food when coadministered with a PPI.
• Take this drug 2 hours before or 10 hours after administration of an H2 receptor antagonist.
• Take this drug 2 hours before or 2 hours after administration of a locally acting antacid.
• Swallow the capsules whole; do not crush or chew the capsules.
• Do not take a missed dose unless it is more than 6 hours until next scheduled dose.
• If vomiting occurs after administration, do not take an additional dose and continue to the next scheduled time for the next dose.

• Store at 20C to 25C (68F to 77F); excursions between 15C and 30C (59F to 86F) are permitted.

• Hepatic function
• Cardiac function