Usual Adult Dose for Non-Small Cell Lung Cancer

400 mg orally once a day
Duration of therapy: Continue until disease progression or unacceptable toxicity

Comments:

• Select patients based on the presence of a RET (rearranged during transfection) gene fusion.
• Information on FDA-approved tests for RET gene fusion is available at http://www.fda.gov/CompanionDiagnostics.

Usual Adult Dose for Thyroid Cancer

400 mg orally once a day
Duration of therapy: Continue until disease progression or unacceptable toxicity

Comments:

• Select patients based on the presence of a RET (rearranged during transfection) gene fusion (thyroid cancer) or RET gene mutation (MTC).
• However, FDA-approved gene fusion tests for RET gene fusion (thyroid cancer) and RET gene mutations are currently not available.

• For the treatment of advanced or metastatic RET mutant medullary thyroid cancer (MTC) who require systemic therapy.
• For the treatment of 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 or older: 400 mg orally once a day
Duration of therapy: Continue until disease progression or unacceptable toxicity

Comments:

• Select patients based on the presence of a RET (rearranged during transfection) gene fusion (thyroid cancer) or RET gene mutation (MTC).
• However, FDA-approved gene fusion tests for RET gene fusion (thyroid cancer) and RET gene mutations are currently not available.

• For the treatment of advanced or metastatic RET mutant medullary thyroid cancer (MTC) who require systemic therapy.
• For the treatment of 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 30 to less than 90 mL/min): No adjustment recommended.
Severe renal impairment (CrCl 15 to less than 30 mL/min): Data not available
ESRD: Data not available

Liver Dose Adjustments

Mild hepatic impairment (total bilirubin less than or equal to upper limit of normal [ULN] and AST greater than ULN; or total bilirubin greater than 1 to 1.5 x ULN and any AST): No adjustment recommended.
Moderate hepatic impairment (total bilirubin greater than 1.5 to 3 x ULN and any AST: Data not available
Severe hepatic impairment (total bilirubin greater than 3 x ULN and any AST): Data not available

Dose Adjustments

DOSE REDUCTIONS FOR ADVERSE REACTIONS:

• First dose reduction: 300 mg orally once a day
• Second dose reduction: 200 mg orally once a day
• Third dose reduction: 100 mg orally once a day
• Discontinue therapy in patients unable to tolerate 100 mg/day.

• Grade 1 or 2: Withhold therapy until resolution; resume at reduced dose
• Grade 3 or 4 or recurrent: Permanently discontinue for confirmed ILD/pneumonitis

• Grade 3: Withhold therapy for Grade 3 hypertension that persists despite optimal antihypertensives; resume at reduced dose when hypertension is controlled
• Grade 4: Permanently discontinue therapy

• Grade 3 or 4: Withhold therapy, monitor transaminases weekly until recovery to Grade 1 or baseline; resume at reduced dose; if hepatotoxicity recurs at Grade 3 or higher, discontinue.

• Grade 3 or 4: Withhold therapy until recovery to baseline, Grade 0, or 1
• Severe or life-threatening hemorrhagic events: Discontinue therapy

• Grade 3 or 4: Withhold therapy until improvement to Grade 2 or less; resume at reduced dose
• Recurrent Grade 4: Permanently discontinue

• Avoid coadministration with combined P-gp and strong CYP450 3A inhibitors.
• If coadministration cannot be avoided, reduce dose of pralsetinib (if current dose is 300 mg/day or 400 mg/day reduce dose to 200 mg/day; if current dose is 200 mg/day reduce dose to 100 mg/day).
• After combined P-gp and strong CYP450 3A inhibitor has been discontinued for 3 to 5 elimination half-lives, resume pralsetinib at dose taken prior to initiating combined P-gp and strong CYP450 3A inhibitor.

• Avoid coadministration with strong CYP450 3A inducers.
• If coadministration with a strong CYP450 3A inducer cannot be avoided, increase the starting dose of pralsetinib to double the current dose starting on Day 7 of coadministration.
• After CYP450 3A inducer has been discontinued for at least 14 days, resume pralsetinib at dose taken prior to initiating CYP450 3A inducer.

Precautions

CONTRAINDICATIONS: None

Safety and efficacy have not been established in patients younger than 12 years for thyroid cancer.
Safety and efficacy have not been established in patients younger than 18 years for NSCLC.

Consult WARNINGS section for additional precautions.

Dialysis

Data not available

Other Comments

Administration advice:

• Take orally on an empty stomach; no food should be consumed for at least 2 hours before and at least 1 hour after dosing

• Do not take an additional dose if vomiting occurs, but continue with next dose as scheduled

• The use of this drug is under accelerated approval based on overall response rate and duration of response. Continued approval for use in NSCLC and thyroid cancer may be contingent upon verification and description of clinical benefit in confirmatory trials.

• Monitor for pulmonary symptoms
• Monitor blood pressure after 1 week, and monthly thereafter; and as clinically indicated
• Obtain AST and ALT at baseline, every 2 weeks during first 3 months, then monthly thereafter; and as clinically indicated
• Monitor at-risk patients for tumor lysis syndrome
• Monitor growth plates in adolescent patients with open growth plates

• Patients should be instructed to read the US FDA-approved patient labeling (Patient Information).
• Patients should be instructed to report new or worsening respiratory symptoms, bleeding, impaired wound healing, and/or signs of hepatotoxicity.
• Patients should understand they may need to stop therapy prior to surgery.
• Women of childbearing potential and males with female partners of reproductive potential should be advised on effective contraception.