Gavreto (pralsetinib)

If adverse reactions occur during pralsetinib therapy, temporary interruption of therapy, dosage reduction, and/or permanent discontinuance of the drug may be necessary. If dosage reduction is required, the dosage of pralsetinib should be reduced as described in Table 1.

Table 1. Dosage Reduction for Pralsetinib Toxicity.

Dose Reduction Level Recommended Dosage Reduction First 300 mg once daily Second 200 mg once daily Third 100 mg once daily Fourth Permanently discontinue pralsetinib

The following Dosage Modification for Pralsetinib Toxicity table indicates the recommended dosage modification (i.e., temporary interruption of therapy, dosage reduction, discontinuance of therapy) for certain adverse effects according to severity.

Table 2. Dosage Modification for Pralsetinib Toxicity

Adverse Reaction and Severity Modification Serious Infections, Including Opportunistic Infections Grade 2 or 3 Withhold therapy; when serious infections resolve, resume at reduced dosage (see Table 1) Grade 4 Permanently discontinue therapy Pulmonary Effects Grade 1 or 2 interstitial lung Withhold therapy; when interstitial disease or pneumonitis lung disease or pneumonitis resolves, resume at reduced dosage (see Table 1) If grade 1 or 2 interstitial lung disease or pneumonitis recurs, permanently discontinue therapy Grade 3 or 4 interstitial lung Permanently discontinue therapy disease or pneumonitis Hepatotoxicity Grade 3 or 4 Withhold therapy and monitor AST and ALT concentrations once weekly When the toxicity resolves to baseline or grade 1, resume at reduced dosage (see Table 1) If toxicity recurs at grade 3 or higher, discontinue therapy Hypertension Grade 3 Withhold therapy if grade 3 hypertension occurs despite optimal antihypertensive therapy When hypertension is controlled, resume at reduced dosage (see Table 1) Grade 4 Discontinue therapy Hemorrhagic Events Grade 3 or 4 Withhold therapy until toxicity improves to baseline or grade 1 or less If severe or life-threatening hemorrhagic events occur, discontinue therapy Growth Plate Abnormality Any grade Consider interrupting or discontinuing therapy based on severity and individual risk-benefit assessment Other Toxicity Grade 3 or 4 Withhold therapy until toxicity improves to baseline or grade 2 or less; resume at reduced dosage (see Table 1) If grade 4 toxicity recurs, permanently discontinue therapy

Pralsetinib is administered orally once daily on an empty stomach (i.e., at least 2 hours after and at least 1 hour before food).

If a dose of pralsetinib is missed, the missed dose should be taken as soon as it is remembered on the same day and the next dose should be taken at the regularly scheduled time. If a dose is vomited following administration, an additional dose should not be administered to make up for the vomited dose and the next dose should be taken at the regularly scheduled time.

Pralsetinib capsules should be stored at 20-25degreesC (excursions permitted between 15-30degreesC).

No dosing information is available for this tab.

No dosing information is available for this tab.

Pralsetinib is metabolized principally by CYP3A4 and to a lesser extent by CYP isoenzymes 2D6 and 1A2. In vitro studies indicate that pralsetinib is a substrate and inhibitor of P-gp and breast cancer resistance protein (BCRP). Pralsetinib is also an inhibitor of organic anion transporting peptide (OATP) 1B1, OATP1B3, organic anion transporter (OAT)1, multidrug and toxin extrusion (MATE)1, MATE2-K, and bile salt efflux pump (BSEP). Pralsetinib is not an inhibitor of organic cation transporter (OCT) 1, OCT2, and OAT1A3.

In vitro studies indicate that pralsetinib is a time-dependent inhibitor of CYP3A and an inhibitor of CYP isoenzymes 2C8, 2C9, and 3A. Pralsetinib is an inducer of CYP isoenzymes 2C8, 2C9, and 3A. Pralsetinib does not inhibit CYP isoenzymes 1A2, 2B6, 2C19, or 2D6 and does not induce 1A2, 2B6, or 2C19.

There are no contraindication interactions for this drug.

There are no severe interactions for this drug.

There are no moderate interactions for this drug.

*None.

There are no contraindication contraindications for this drug.

There are no severe contraindications for this drug.

There are no moderate contraindications for this drug.

The most common adverse reactions (>=25%) were musculoskeletal pain, constipation, hypertension, diarrhea, fatigue, edema, pyrexia, and cough. The most common grade 3 or 4 laboratory abnormalities (>=2%) were decreased lymphocytes, decreased neutrophils, decreased phosphate, decreased hemoglobin, decreased leukocytes, decreased sodium, decreased calcium (corrected), increased ALT/AST concentrations, decreased platelets, increased alkaline phosphatase, increased or decreased potassium, and increased bilirubin.

There are no severe adverse reactions for this drug.

There are no less severe adverse reactions for this drug.

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Safety and efficacy of pralsetinib for the treatment of metastatic rearranged during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC) have not been established in pediatric patients.

Safety and efficacy of pralsetinib for the treatment of RET fusion-positive thyroid cancer in pediatric patients 12 years of age or older is supported by extrapolation of data from a clinical study evaluating pralsetinib in adults and additional pharmacokinetic data in pediatric patients 12 years of age or older demonstrating that age and body weight had no clinically meaningful effect on the pharmacokinetics of the drug. Systemic exposure of pralsetinib is expected to be similar between adults and pediatric patients aged 12 years and older. The course of RET fusion-positive thyroid cancer is sufficiently similar in adults and pediatric patients to allow extrapolation of data in adults to pediatric patients.

Skeletal (i.e., physeal dysplasia) and tooth abnormalities (i.e., fractures, dentin matrix alteration, ameloblast/odontoblast degeneration, necrosis) have been observed in immature animals receiving pralsetinib at exposure levels similar to human exposure at the 400 mg once daily dosage. The manufacturer recommends monitoring growth plates in adolescents with open growth plates. If growth plate abnormalities occur, interruption or discontinuance of therapy should be considered based on the severity of the abnormality and individual risk-benefit assessment.

Pralsetinib may cause fetal harm if administered to pregnant women based on its mechanism of action and animal findings.

The manufacturer states that a pregnancy test should be performed prior to initiation of pralsetinib therapy in females of reproductive potential. Patients should be apprised of the potential hazard to the fetus if pralsetinib is used during pregnancy.

It is not known whether pralsetinib or its metabolites are distributed into human milk. The effects of the drug on nursing infants or on the production of milk are unknown. Because of the potential for adverse reactions to pralsetinib in nursing infants, women should be advised not to breast-feed while receiving the drug and for 1 week after the final dose.

The manufacturer makes no specific dosage recommendation for geriatric patients.

In the ARROW study, 31% of patients receiving pralsetinib 400 mg once daily were 65 years of age or older and 7% were 75 years of age or older. No differences in pharmacokinetics, safety, or efficacy were observed between geriatric patients and younger adults.