Note: Select patients for pralsetinib treatment based on the presence of a RET gene fusion (non-small cell lung cancer or thyroid cancer) or RET gene mutation (medullary thyroid cancer). Withhold pralsetinib 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 has occurred.
Non-small cell lung cancer, metastatic, RET fusion-positive: Oral: 400 mg once daily until disease progression or unacceptable toxicity.
Thyroid cancer, advanced or metastatic, RET fusion-positive: Oral: 400 mg once daily until disease progression or unacceptable toxicity.
Thyroid cancer (medullary), advanced or metastatic, RET-mutant: Oral: 400 mg once daily until disease progression or unacceptable toxicity.
Missed dose: If a dose is missed, administer as soon as possible on the same day; resume the regular daily pralsetinib dose schedule the following day. If vomiting occurs after pralsetinib administration, do not take an additional dose and continue to the next scheduled time for the next dose.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
CrCl ≥30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling; however, CrCl 30 to 89 mL/minute had no effect on pralsetinib exposure.
CrCl 15 to 30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling.
CrCl <15 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Hepatic impairment at treatment initiation:
Mild (total bilirubin ≤ ULN with AST > ULN or total bilirubin >1 to 1.5 times ULN with any AST) impairment: No dosage adjustment is required.
Moderate (total bilirubin >1.5 to 3 times ULN and any AST) or severe (total bilirubin >3 times ULN and any AST) impairment: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Hepatotoxicity during treatment: Grade 3 or 4: Withhold pralsetinib and monitor AST and ALT once weekly until resolves to grade 1 or baseline. Resume pralsetinib at a reduced dose. If ≥ grade 3 hepatotoxicity recurs, discontinue pralsetinib. See recommended pralsetinib dosage reduction levels in "Dosing - Adjustment for Toxicity."
(For additional information see "Pralsetinib: Pediatric drug information")
Note: Select patients for pralsetinib treatment based on the presence of a RET gene fusion (thyroid cancer) or RET gene mutation (medullary thyroid cancer). Withhold pralsetinib 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 has occurred.
Thyroid cancer; advanced or metastatic, RET fusion-positive: Children ≥12 years and Adolescents: Oral: 400 mg once daily until disease progression or unacceptable toxicity.
Thyroid cancer (medullary), advanced or metastatic, RET-mutant: Children ≥12 years and Adolescents: Oral: 400 mg once daily until disease progression or unacceptable toxicity.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose adjustment or avoidance. Consult drug interactions database for more information.
Dosing adjustment for toxicity:
|
Dose reduction level |
Recommended dosage |
|---|---|
|
Usual (initial dose) |
400 mg once daily |
|
First dose reduction level |
300 mg once daily |
|
Second dose reduction level |
200 mg once daily |
|
Third dose reduction level |
100 mg once daily |
|
Permanently discontinue pralsetinib if unable to tolerate 100 mg once daily. | |
|
Toxicity |
Severity |
Pralsetinib dose modification |
|---|---|---|
|
Hemorrhagic events |
Grade 3 or 4 |
Withhold pralsetinib until recovery to baseline or grade 0 or 1. Permanently discontinue pralsetinib for severe or life-threatening hemorrhagic events. |
|
Hypertension |
Grade 3 |
Initiate or optimize antihypertensive therapy. Withhold pralsetinib for grade 3 hypertension that persists despite management with optimal antihypertensive therapy. Resume pralsetinib at a reduced dose when hypertension is controlled. |
|
Grade 4 |
Discontinue pralsetinib. | |
|
Pulmonary toxicity (interstitial lung disease [ILD])/pneumonitis) |
Grade 1 or 2 |
Withhold pralsetinib until resolution, then resume pralsetinib at a reduced dose. Permanently discontinue pralsetinib for recurrent ILD/pneumonitis. |
|
Grade 3 or 4 |
Permanently discontinue pralsetinib for confirmed ILD/pneumonitis. | |
|
Other adverse reactions |
Grade 3 or 4 |
Withhold pralsetinib until improvement to ≤ grade 2, then resume pralsetinib at a reduced dose. Permanently discontinue pralsetinib for recurrent grade 4 adverse reactions. |
Children ≥12 years and Adolescents: Oral:
CrCl ≥30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling; however, based on adult data, CrCl 30 to 89 mL/minute had no effect on pralsetinib exposure.
CrCl 15 to 30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling.
CrCl <15 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Children ≥12 years and Adolescents: Oral:
Baseline hepatic impairment:
Mild (total bilirubin ≤ ULN with AST > ULN or total bilirubin >1 to 1.5 times ULN with any AST) impairment: No dosage adjustment is required.
Moderate (total bilirubin >1.5 to 3 times ULN and any AST) or severe (total bilirubin >3 times ULN and any AST) impairment: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Hepatotoxicity during treatment: Grade 3 or 4: Withhold pralsetinib and monitor AST and ALT once weekly until resolves to grade 1 or baseline. Resume pralsetinib at a reduced dose. If ≥ grade 3 hepatotoxicity recurs, discontinue pralsetinib. See recommended pralsetinib dosage reduction levels in "Dosing Adjustment for Toxicity."
Refer to adult dosing.
|
Dose reduction |
Recommended dosage |
|---|---|
|
Usual (initial dose) |
400 mg once daily |
|
First dose reduction level |
300 mg once daily |
|
Second dose reduction level |
200 mg once daily |
|
Third dose reduction level |
100 mg once daily |
|
Permanently discontinue pralsetinib if unable to tolerate 100 mg once daily. | |
|
Toxicity |
Severity |
Pralsetinib dose modification |
|---|---|---|
|
Hemorrhagic events |
Grade 3 or 4 |
Withhold pralsetinib until recovery to baseline or grade 0 or 1. Permanently discontinue pralsetinib for severe or life-threatening hemorrhagic events. |
|
Hypertension |
Grade 3 |
Initiate or optimize hypertensive therapy. Withhold pralsetinib for grade 3 hypertension that persists despite management with optimal antihypertensive therapy. Resume pralsetinib at a reduced dose when hypertension is controlled. |
|
Grade 4 |
Discontinue pralsetinib. | |
|
Pulmonary toxicity (interstitial lung disease [ILD])/pneumonitis) |
Grade 1 or 2 |
Withhold pralsetinib until resolution, then resume pralsetinib at a reduced dose. Permanently discontinue pralsetinib for recurrent ILD/pneumonitis. |
|
Grade 3 or 4 |
Permanently discontinue pralsetinib for confirmed ILD/pneumonitis. | |
|
Other adverse reactions |
Grade 3 or 4 |
Withhold pralsetinib until improvement to ≤ grade 2, then resume pralsetinib at a reduced dose. Permanently discontinue pralsetinib for recurrent grade 4 adverse reactions. |
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Gavreto: 100 mg [contains fd&c blue #1 (brilliant blue)]
No
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Gavreto: 100 mg [contains fd&c blue #1 (brilliant blue)]
Pralsetinib is available through a specialty pharmacy network and specialty distributors; information may be found at https://gavreto.com/.
Oral: Administer on an empty stomach at least 1 hour before and at least 2 hours after a meal or food.
Oral: Administer on an empty stomach; no food or meal at least 2 hours before dose and at least 1 hour after. If vomiting occurs after pralsetinib administration, do not take an additional dose; continue to the next scheduled time for the next dose.
Missed dose: If a dose is missed, administer as soon as possible on the same day; resume the regular daily pralsetinib dose schedule the following day.
This medication is not on the NIOSH (2016) list; however, it may meet the criteria for a hazardous drug. Pralsetinib may cause reproductive toxicity and teratogenicity.
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.
Non-small cell lung cancer, metastatic RET fusion-positive: Treatment of metastatic RET fusion-positive non-small cell lung cancer (NSCLC) in adults as detected by an approved test.
Thyroid cancer, advanced or metastatic, RET fusion-positive: Treatment of advanced or metastatic RET fusion-positive thyroid cancer in pediatric patients ≥12 years of age and adults who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate).
Thyroid cancer (medullary), advanced or metastatic, RET-mutant: Treatment of advanced or metastatic RET-mutant medullary thyroid cancer in pediatric patients ≥12 years of age and adults who require systemic therapy.
Pralsetinib may be confused with pazopanib, pemigatinib, pexidartinib, ponatinib, pralatrexate, ripretinib, selpercatinib.
This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its lists of drug classes that have a heightened risk of causing significant patient harm when used in error.
Hemorrhage has occurred with pralsetinib, including some grade 3/4 events and rare fatal events.
Hepatotoxicity, including severe hepatotoxicity (grade 3 or grade 4), has been observed with pralsetinib. Increased serum alanine aminotransferase (ALT) and increased serum aspartate aminotransferase (AST) commonly occurs. Some patients required treatment interruption, dose reduction and/or permanent discontinuation, depending on severity of hepatoxicity.
Onset: Varied; median time to first onset of elevated AST was 15 days (range: 5 days to 1.5 years); the median time to first onset of elevated ALT was 22 days (range: 7 days to 1.7 years).
Hypertension commonly occurs with use, with almost half of these patients developing grade 3 hypertension. Although antihypertensive medication was the most common method used to manage treatment-emergent hypertension, some patients required treatment interruption, dose reduction and/or permanent discontinuation, depending on severity.
Mechanism: Dose-related; exact mechanism is not established.
Risk factors:
• Preexisting uncontrolled hypertension
Severe, life-threatening, and potentially fatal interstitial lung disease (ILD)/pneumonitis may occur with pralsetinib. Pneumonitis was commonly reported, including some grade 3 and 4 events; fatal pneumonitis occurred rarely. Withhold therapy and promptly evaluate patients with symptoms indicative of ILD. Therapy interruption, dose reduction, and/or permanent pralsetinib discontinuation may be necessary based on the severity of confirmed ILD.
Cases of tumor lysis syndrome have been reported in patients treated with pralsetinib for medullary thyroid cancer.
Risk factors:
• Presence of rapidly growing tumors
• High tumor burden
• Renal dysfunction
• Dehydration
Pralsetinib may have the potential to adversely affect wound healing. Due to this concern, recommendations regarding withholding therapy prior to elective surgery and/or after major surgery exist.
Mechanism: Exact mechanism is unknown; vascular endothelial growth factor (VEGF) receptor inhibitors are associated with impaired wound healing.
Risk factors:
• Major surgery
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Cardiovascular: Edema (20% to 29%), hypertension (28% to 40%)
Dermatologic: Skin rash (24%)
Endocrine & metabolic: Decreased serum albumin (36% to 41%), decreased serum calcium (corrected: 39% to 70%), decreased serum magnesium (27%), decreased serum phosphate (28% to 35%), decreased serum sodium (28% to 29%), increased serum phosphate (10% to 40%), increased serum potassium (26%)
Gastrointestinal: Abdominal pain (17%), constipation (35% to 41%), decreased appetite (15%), diarrhea (24% to 34%), dysgeusia (17%), nausea (17%), stomatitis (17%; grade 3/4: <1%), xerostomia (16% to 17%)
Hematologic & oncologic: Decreased hemoglobin (58% to 63%; grades 3/4: 9% to 13%), decreased neutrophils (59% to 61%; grades 3/4: 16%), decreased platelet count (27% to 31%; grades 3/4: 3%), lymphocytopenia (56% to 67%; grades 3/4: 19% to 27%), tumor lysis syndrome (<15%)
Hepatic: Increased serum alanine aminotransferase (43% to 49%), increased serum alkaline phosphatase (22% to 42%), increased serum aspartate aminotransferase (69% to 74%), increased serum bilirubin (24%)
Nervous system: Dizziness (19%), fatigue (35% to 38%), headache (24%), peripheral neuropathy (20%)
Neuromuscular & skeletal: Increased creatine phosphokinase in blood specimen (<15%), musculoskeletal pain (32% to 42%)
Renal: Increased serum creatinine (33% to 41%)
Respiratory: Cough (23% to 27%), dyspnea (22%), pneumonia (17%)
Miscellaneous: Fever (20% to 22%)
1% to 10%:
Genitourinary: Urinary tract infection
Hematologic & oncologic: Hemorrhage (grades ≥3: 3%)
Hepatic: Ascites, severe hepatotoxicity (2%)
Infection: Sepsis
Respiratory: Pneumonitis (10%)
Frequency not defined:
Cardiovascular: Syncope
Gastrointestinal: Vomiting
Hematologic & oncologic: Leukopenia
There are no contraindications listed in the manufacturer's US labeling.
Canadian labeling: Hypersensitivity to pralsetinib or any component of the formulation.
Concerns related to adverse effects:
• Hypertension: Optimize BP prior to initiating treatment; do not initiate pralsetinib in patients with uncontrolled hypertension.
• Tumor lysis syndrome: Cases of tumor lysis syndrome (TLS) have been reported with pralsetinib in patients with medullary thyroid cancer. The risk for TLS is increased in patients with rapidly growing tumors, a high tumor burden, kidney dysfunction, or dehydration. Assess risk for TLS; consider appropriate prophylaxis (including hydration) and manage as clinically indicated.
Dosage form specific issues:
• Propylene glycol: Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated with hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP 1997; Zar 2007). See manufacturer’s labeling.
Other warnings/precautions:
• RET gene status: Select patients for pralsetinib treatment based on the presence of a RET gene fusion (non-small cell lung cancer or thyroid cancer) or RET gene mutation (medullary thyroid cancer). Information on FDA-approved tests is available at http://www.fda.gov/CompanionDiagnostics.
Substrate of BCRP/ABCG2, CYP1A2 (minor), CYP2D6 (minor), CYP3A4 (major), P-glycoprotein/ABCB1 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Androgens: Hypertension-Associated Agents may enhance the hypertensive effect of Androgens. Risk C: Monitor therapy
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Pralsetinib. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of Pralsetinib. Management: Avoid concomitant use of pralsetinib with strong CYP3A4 inducers when possible. If combined, increase the starting dose of pralsetinib to double the current pralsetinib dosage starting on day 7 of coadministration. Risk D: Consider therapy modification
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Pralsetinib. Risk X: Avoid combination
Inhibitors of CYP3A4 (Moderate) and P-glycoprotein: May increase the serum concentration of Pralsetinib. Risk C: Monitor therapy
Inhibitors of CYP3A4 (Strong) and P-glycoprotein: May increase the serum concentration of Pralsetinib. Management: Avoid concomitant use if possible. If combined, reduce the pralsetinib dose. If taking 400 mg or 300 mg once daily, reduce to 200 mg once daily. If taking 200 mg once daily, reduce to 100 mg once daily. Risk D: Consider therapy modification
Solriamfetol: May enhance the hypertensive effect of Hypertension-Associated Agents. Risk C: Monitor therapy
Following administration of a single 200 mg pralsetinib dose with a high-fat meal (~800 to 1,000 calories with 50% to 60% of calories from fat), the mean Cmax and AUC0-inf were increased by 104% and 122%, respectively, compared to the fasting state; the median Tmax was delayed from 4 to 8.5 hours. Management: Administer pralsetinib on an empty stomach at least 1 hour before and at least 2 hours after a meal or food.
Evaluate pregnancy status prior to use in females of reproductive potential.
Females of reproductive potential should use effective nonhormonal contraception during therapy and for 2 weeks after the last pralsetinib dose. Males with female partners of reproductive potential should use effective contraception during therapy and for 1 week after the last dose of pralsetinib.
Based on the mechanism of action and data from animal reproduction studies, in utero exposure to pralsetinib may cause fetal harm.
It is not known if pralsetinib is present in breast milk.
Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer during therapy and for 1 week after the last pralsetinib dose.
Evaluate RET gene fusion status (non-small cell lung cancer or thyroid cancer) or RET gene mutation (medullary thyroid cancer). Monitor ALT and AST prior to treatment initiation, every 2 weeks during the first 3 months, then monthly thereafter, and as clinically indicated. Evaluate pregnancy status prior to use in females of reproductive potential. Monitor BP at baseline, after 1 week, at least monthly thereafter, and as clinically indicated. Monitor for signs/symptoms of interstitial lung disease/pneumonitis (eg, dyspnea, cough, and fever), hemorrhage, tumor lysis syndrome (in patients with medullary thyroid cancer), and impaired wound healing. Monitor adherence.
The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
Pralsetinib inhibits wild-type RET (REarranged during Transfection), oncogenic RET fusions (CCDC6-RET) and RET mutations (RET V804L, RET V804M, and RET M918T); in enzyme assays, pralsetinib also inhibited DDR1, TRKC, FLT3, JAK1-2, TRKA, VEGFR2, PDGFRb, and FGFR1. Certain activating point mutations in RET or chromosomal rearrangements involving in-frame fusions of RET can result in constitutively activated chimeric RET fusion proteins, which may act as oncogenic drivers, promoting tumor cell line proliferation. Pralsetinib has demonstrated antitumor activity in cells harboring oncogenic RET fusions or mutations including CCDC6-RET, KIF5B-RET, RET M918T, RET C634W, RET V804L, and RET V804M.
Note: Pharmacokinetic data in pediatric patients ≥12 years was shown to be similar to adult patients.
Distribution: Adults: Vd/F: 303 L.
Protein binding: ~97%.
Metabolism: Predominantly via CYP3A4 and to a lesser extent by CYP2D6 and CYP1A2.
Half-life elimination: Adults: Single dose: ~16 hours; multiple doses: ~20 hours.
Time to peak: Adults: 2 to 4 hours.
Excretion: Adults: Feces: ~73% (66% as unchanged drug); urine: ~6% (~5% as unchanged drug).
Clearance: Adults: 10.9 L/hour.
Capsules (Gavreto Oral)
100 mg (per each): $202.17
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