Dosing & Uses
Dosage Forms & Strengths
capsule
- 100mg
Non-Small Cell Lung Cancer
Indicated for metastatic rearranged during transfection (RET) gene-positive non-small cell lung cancer (NSCLC)
400 mg PO qDay on an empty stomach
Continue until disease progression or until unacceptable toxicity
Medullary Thyroid Cancer
Indicated for advanced or metastatic RET-mutant medullary thyroid cancer (MTC) in adults who require systemic therapy
400 mg PO qDay
Continue until disease progression or until unacceptable toxicity
Thyroid Cancer
Indicated for advanced or metastatic RET-fusion positive thyroid cancer in adults who require systemic therapy and are radioactive iodine-refractory (if radioactive iodine is appropriate)
400 mg PO qDay
Continue until disease progression or until unacceptable toxicity
Dosage Modifications
Dosage modifications for adverse reactions
- First dose reduction: 300 mg PO qDay
- Second dose reduction: 200 mg PO qDay
- Third dose reduction: 100 mg PO qDay
- Unable to tolerate 100 mg qDay: Permanently discontinue
Interstitial lung disease (ILD)/pneumonitis
- Grade 1 or 2: Withhold until resolution; resume at reduced dose
- Grade 3 or 4 or recurrent ILD/pneumonitis: Permanent discontinue
Hypertension
- Grade 3: Withhold for persistent Grade 3 hypertension despite optimal antihypertensive therapy; resume at reduced dose once hypertension controlled
- Grade 4: Discontinue
Hepatoxicity
- Grade 3 or 4: Withhold and monitor AST/ALT once weekly until resolution to Grade ≤1
- Resume at reduced dose
- If Grade ≥3 hepatotoxicity recurs, discontinue
Hemorrhagic events
- Grade 3 or 4: Withhold until recovery to baseline or Grade ≤1
- Discontinue for severe or life-threatening hemorrhagic events
Other adverse reactions
- Grade 3 or 4: Withhold until recovery to Grade ≤2; resume at reduced dose
- Recurrent Grade 4: Permanently discontinue
Strong CYP3A4 inhibitors or combined P-gp and strong CYP3A4 inhibitors
- Avoid coadministration
-
Dosage modification if unable to avoid combined P-gp and strong CYP3A4 inhibitors
- If current pralsetinib dose is 300 or 400 mg qDay, reduce to 200 mg qDay
- If current pralsetinib dose is 200 mg qDay, reduce to 100 mg qDay
- After inhibitor has been discontinued for 3-5 elimination half-lives, resume at dose taken before initiating combined P-gp and strong CYP3A inhibitor
Strong CYP3A4 inducers
- Avoid coadministration
- If unable to avoid, double current pralsetinib dose starting on Day 7 of coadministration with strong CYP3A inducer
- After inducer has been discontinued for at least 14 days, resume pralsetinib at dose taken before initiating strong CYP3A inducer
Renal impairment
- Mild-to-moderate (CrCl 30-89 mL/min): No dosage adjustment necessary
- Severe (CrCl <15 mL/min): Not studied
Hepatic impairment
- Mild (total bilirubin ≤ULN and AST >ULN OR total bilirubin >1-1.5x ULN and any AST): No dosage adjustment necessary
- Moderate-to-severe (total bilirubin >1.5x ULN and any AST): Not studied
Dosing Considerations
Verify pregnancy status of females of reproductive potential before initiation
Patient selection
- Select patients based on presence of RET gene fusion
- Information on FDA-approved tests is available at http://www.fda.gov/CompanionDiagnostics
Medullary Thyroid Cancer
Indicated for advanced or metastatic RET-mutant medullary thyroid cancer (MTC) in adults and adolescents aged ≥12 years who require systemic therapy
<12 years: Safety and efficacy not established
≥12 years
- 400 mg PO qDay
- Continue until disease progression or until unacceptable toxicity
Thyroid Cancer
Indicated for advanced or metastatic RET-fusion positive thyroid cancer in adults and adolescents aged ≥12 years who require systemic therapy and are radioactive iodine-refractory (if radioactive iodine is appropriate)
<12 years: Safety and efficacy not established
≥12 years
- 400 mg PO qDay
- Continue until disease progression or until unacceptable toxicity
Dosage Modifications
Dosage modifications for adverse reactions
- First dose reduction: 300 mg PO qDay
- Second dose reduction: 200 mg PO qDay
- Third dose reduction: 100 mg PO qDay
- Unable to tolerate 100 mg qDay: Permanently discontinue
Interstitial lung disease (ILD)/pneumonitis
- Grade 1 or 2: Withhold until resolution; resume at reduced dose
- Grade 3 or 4 or recurrent ILD/pneumonitis: Permanently discontinue
Hypertension
- Grade 3: Withhold for persistent Grade 3 hypertension despite optimal antihypertensive therapy; resume at reduced dose once hypertension controlled
- Grade 4: Discontinue
Hepatoxicity
- Grade 3 or 4: Withhold and monitor AST/ALT once weekly until resolution to Grade ≤1
- Resume at reduced dose
- If Grade ≥3 hepatotoxicity recurs, discontinue
Hemorrhagic events
- Grade 3 or 4: Withhold until recovery to baseline or Grade ≤1
- Discontinue for severe or life-threatening hemorrhagic events
Other adverse reactions
- Grade 3 or 4: Withhold until recovery to Grade ≤2; resume at reduced dose
- Recurrent Grade 4: Permanently discontinue
Strong CYP3A4 inhibitors or combined P-gp and strong CYP3A4 inhibitors
- Avoid coadministration
-
Dosage modification if unable to avoid combined P-gp and strong CYP3A4 inhibitors
- If current pralsetinib dose is 300 or 400 mg qDay, reduce to 200 mg qDay
- If current pralsetinib dose is 200 mg qDay, reduce to 100 mg qDay
- After inhibitor has been discontinued for 3-5 elimination half-lives, resume at dose taken before initiating combined P-gp and strong CYP3A inhibitor
Strong CYP3A4 inducers
- Avoid coadministration
- If unable to avoid, double current pralsetinib dose starting on Day 7 of coadministration with strong CYP3A inducer
- After inducer has been discontinued for at least 14 days, resume pralsetinib at dose taken before initiating strong CYP3A inducer
Renal impairment
- Mild-to-moderate (CrCl 30-89 mL/min): No dosage adjustment necessary
- Severe (CrCl <15 mL/min): Not studied
Hepatic impairment
- Mild (total bilirubin ≤ULN and AST >ULN OR total bilirubin >1-1.5x ULN and any AST): No dosage adjustment necessary
- Moderate-to-severe (total bilirubin >1.5x ULN and any AST): Not studied
Dosing Considerations
Verify pregnancy status of females of reproductive potential before initiation
Patient selection
- Select patients based on presence of RET gene fusion
- Information on FDA-approved tests is available at http://www.fda.gov/CompanionDiagnostics
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Adverse Effects
>10%
All grades
-
NSCLC
- Increased AST (69%)
- Increased ALT (46%)
- Decreased hemoglobin (54%)
- Decreased lymphocytes (52%)
- Decreased neutrophils (52%)
- Increased creatinine (42%)
- Increased alkaline phosphatase (40%)
- Constipation (35%)
- Fatigue (35%)
- Musculoskeletal pain (32%)
- Decreased calcium (corrected) (29%)
- Hypertension (28%)
- Decreased sodium (27%)
- Decreased phosphate (27%)
- Decreased platelets (26%)
- Diarrhea (24%)
- Cough (23%)
- Pyrexia (20%)
- Edema (20%)
- Pneumonia (17%)
- Dry mouth (16%)
-
Thyroid cancer
- Decreased calcium (corrected) (70%)
- Increased AST (69%)
- Decreased lymphocytes (67%)
- Decreased hemoglobin (63%)
- Decreased neutrophils (59%)
- Increased ALT (43%)
- Musculoskeletal pain (42%)
- Constipation (41%)
- Increased creatinine (41%)
- Decreased albumin (41%)
- Hypertension (40%)
- Increased phosphate (40%)
- Fatigue (38%)
- Diarrhea (34%)
- Decreased platelets (31%)
- Edema (29%)
- Decreased sodium (28%)
- Decreased phosphate (28%)
- Cough (27%)
- Decreased magnesium (27%)
- Decreased magnesium (27%)
- Increased potassium (26%)
- Headache (24%)
- Rash (24%)
- Increased bilirubin (24%)
- Increased alkaline phosphatase (22%)
- Dyspnea (22%)
- Pyrexia (22%)
- Peripheral neuropathy (20%)
- Dizziness (19%)
- Dysgeusia (17%)
- Abdominal pain (17%)
- Dry mouth (17%)
- Stomatitis (17%)
- Nausea (17%)
- Decreased appetite (15%)
- Tumor lysis syndrome (≤15%)
- Increased creatinine phosphokinase (≤15%)
Grade 3-4
-
NSCLC
- Decreased lymphocytes (20%)
- Hypertension (14%)
-
Thyroid cancer
- Decreased lymphocytes (27%)
- Hypertension (21%)
- Decreased neutrophils (16%)
- Decreased hemoglobin (13%)
1-10%
All grades
-
NSCLC
- Hyperphosphatemia (10%)
- Pneumonitis (10%)
Grade 3-4
-
NSCLC
- Decreased neutrophils (10%)
- Decreased phosphate (9%)
- Pneumonia (8%)
- Decreased hemoglobin (5%)
- Decreased sodium (3.2%)
- Diarrhea (3.2%)
- Pneumonitis (2.7%)
- Fatigue (2.3%)
- Decreased calcium (corrected) (2.2%)
- Increased ALT (2.1%)
- Sepsis (≥2%)
- Increased AST (1.1%)
- Increased creatinine (1.1%)
- Increased alkaline phosphatase (1.1%)
- Constipation (1%)
-
Thyroid cancer
- Decreased phosphate (8%)
- Fatigue (6%)
- Diarrhea (5%)
- Increased AST (4.3%)
- Increased ALT (3.6%)
- Decreased platelets (2.9%)
- Pyrexia (2.2%)
- Dyspnea (2.2%)
- Decreased sodium (2.2%)
- Decreased albumin (1.5%)
- Cough (1.4%)
- Increased potassium (1.4%)
- Increased bilirubin (1.4%)
- Increased alkaline phosphatase (1.4%)
<1%
Grade 3-4
-
NSCLC
- Cough (0.5%)
-
Thyroid cancer
- Musculoskeletal pain (0.7%)
- Constipation (0.7%)
- Abdominal pain (0.7%)
- Stomatitis (0.7%)
- Nausea (0.7%)
- Dizziness (0.7%)
- Decreased magnesium (0.7%)
Warnings
Contraindications
None
Cautions
Severe, life-threatening, and fatal ILD/pneumonitis can occur; monitor for pulmonary symptoms indicative of ILD/pneumonitis
Serious hepatic adverse reactions reported; monitor AST/ALT before initiation, every 2 weeks during first 2 months, and then monthly thereafter and as clinically indicated
May cause serious, including fatal, hemorrhagic events
Based on findings from animal studies and its mechanism of action, may cause fetal harm when administered to pregnant females
Tumor lysis syndrome reported in MTC-treated patients; closely monitor patients at risk, consider appropriate prophylaxis including hydration, and treat as clinically indicated
Hypertension
- Hypertension occurred; treatment-emergent hypertension was mostly managed with antihypertensive therapy
- Do not initiate with uncontrolled hypertension
- Optimize blood pressure (BP) before initiation
- Monitor BP after 1 week, then at least monthly thereafter and as clinically indicated
- Initiate or adjust antihypertensive therapy as needed
Impaired wound healing
- Impaired wound healing can occur in patients who receive drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway
- May have potential to adversely affect wound healing
- Withhold for at least 5 days prior to elective surgery
- Do not administer for at least 2 weeks following major surgery and until adequate wound healing
- Safety of resumption after resolution of wound healing complications has not been established
Drug interaction overview
- Pralsetinib is a CYP3A4 and P-gp substrate
-
Strong CYP3A4 inhibitors
- Avoid coadministration
- Strong CYP3A inhibitors increase exposure and risk of toxicities to pralsetinib
-
Combined P-gp and strong CYP3A inhibitors
- Avoid coadministration; if unable to avoid, decrease pralsetinib dose
- Combined P-gp and strong CYP3A inhibitors increase plasma concentrations and effects of pralsetinib
-
Strong CYP3A4 inducers
- Avoid coadministration; if unable to avoid, increase pralsetinib dose
- Strong CYP3A inducers decrease exposure to pralsetinib
Pregnancy & Lactation
Pregnancy
Based on animal studies and its mechanism of action, fetal harm may occur when administered to pregnant females
No data available on use in pregnant females to inform drug-associated risk
Verify pregnancy status of females of reproductive potential before initiation
Contraception
- Females of reproductive potential: Use effective nonhormonal contraception during treatment and for 2 weeks after final dose; pralsetinib may render hormonal contraceptives ineffective
- Males with female partners of reproductive potential: Use effective contraception during treatment and for 1 week after final dose
Infertility
- Based on histopathological findings in male and female rats and a dedicated fertility study, fertility may be impaired
Animal data
- Oral pralsetinib administered to pregnant rats during organogenesis resulted in malformation and embryolethality at maternal exposures below human exposure at a dose of 400 mg qDay
- Advise pregnant females of potential risk to fetus
Lactation
There are no data on presence of pralsetinib or its metabolites in human milk, effects on breastfed children, or on milk production
Advise females not to breastfeed during treatment and for 1 week after final dose
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
Selective inhibitor of rearranged during transfection (RET) alterations and resistant mutations; specifically designed to spare VEGFR2 and other kinases with the potential to drive off-target toxicity
Exhibited antitumor activity in cultured cells and animal tumor implantation models harboring oncogenic RET fusions or mutations
Absorption
Peak plasma concentration: 2830 ng/mL (400-mg dose, fasted)
Peak plasma time: 2-4 hr (single 60- to 600-mg dose)
AUC: 43,900 ng⋅hr/mL (400-mg dose, fasted)
Steady-state reached at 3-5 days
Effects of food
Administering with high-fat meal (ie, ~800-1000 calories with 50-60% of calories from fat) delayed peak concentration time and increased peak plasma concentration and AUC
Single 400-mg dose
- Mean peak plasma concentration increased by 104%
- Mean AUC increased by 122%
- Peak plasma time delayed from 4-8.5 hr
Distribution
Vd: 228 L
Protein bound: 97.1%
Blood-to-plasma ratio: 0.6-0.7
Metabolism
Primarily metabolized by CYP3A4 and to lesser extent by CYP2D6 and CYP1A2
Following single oral dose of ~310 mg of radiolabeled pralsetinib to healthy individuals, metabolites from oxidation (M531, M453, M549b) and glucuronidation (M709) were detected as 5%
Elimination
Half-life: 14.7 hr (single dose); 22.2 hr (multiple doses)
Clearance (steady-state): 9.1 L/hr
Excretion: ~73% (urine; 66% unchanged); 6% (feces; 4.8% unchanged)
Administration
Oral Administration
Take on empty stomach (no food intake for at least 2 hr before and 1 hr after dose)
Missed dose: Take as soon as possible on same day; resume regular daily dose schedule thereafter
Vomited dose: Do not take additional dose; continue with next scheduled dose
Storage
Store at 20-25ºC (68-77ºF); excursions are permitted to 15-30ºC (59-86ºF)
Images
Patient Handout
Formulary
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