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Pralsetinib

Class: Antineoplastic Agents
Chemical Name: N-[(1S)-1-[6-(4-fluoropyrazol-1-yl)pyridin-3-yl]ethyl]-1-methoxy-4-[4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]cyclohexane-1-carboxamide
Molecular Formula: C27H32FN9O2
CAS Number: 2097132-93-7
Brands: Gavreto

Medically reviewed by Drugs.com on Sep 21, 2020. Written by ASHP.

Introduction

Pralsetinib is an antineoplastic agent.

Uses for Pralsetinib

Pralsetinib has the following uses:

Pralsetinib is a kinase inhibitor indicated for the treatment of adult patients with metastatic rearranged during transfection (RET) fusion- positive non-small cell lung cancer (NSCLC) as detected by an FDA approved test.

This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

Pralsetinib Dosage and Administration

General

Pralsetinib is available in the following dosage form(s) and strength(s):

Capsules: 100 mg.

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

Select patients for treatment with pralsetinib based on the presence of a RET gene fusion.

The recommended dosage in adults is 400 mg orally once daily on an empty stomach (no food intake for at least 2 hours before and at least 1 hour after taking pralsetinib.

Cautions for Pralsetinib

Contraindications

None.

Warnings/Precautions

Interstitial Lung Disease/pneumonitis

Severe, life-threatening, and fatal interstitial lung disease (ILD)/pneumonitis can occur in patients treated with pralsetinib. Pneumonitis occurred in 10% of patients who received pralsetinib, including 2.7% with Grade 3-4, and 0.5% with fatal reactions.

Monitor for pulmonary symptoms indicative of ILD/pneumonitis. Withhold pralsetinib and promptly investigate for ILD in any patient who presents with acute or worsening of respiratory symptoms which may be indicative of ILD (e.g., dyspnea, cough, and fever). Withhold, reduce dose or permanently discontinue pralsetinib based on severity of confirmed ILD.

Hypertension

Hypertension occurred in 29% of patients, including Grade 3 hypertension in 14% of patients. Overall, 7% had their dose interrupted and 3.2% had their dose reduced for hypertension. Treatment-emergent hypertension was most commonly managed with anti-hypertension medications.

Do not initiate pralsetinib in patients with uncontrolled hypertension. Optimize blood pressure prior to initiating pralsetinib. Monitor blood pressure after 1 week, at least monthly thereafter and as clinically indicated. Initiate or adjust anti-hypertensive therapy as appropriate. Withhold, reduce dose, or permanently discontinue pralsetinib based on the severity.

Hepatotoxicity

Serious hepatic adverse reactions occurred in 2.1% of patients treated for pralsetinib. Increased AST occurred in 69% of patients, including Grade 3 or 4 in 5.4% and increased ALT occurred in 46% of patients, including Grade 3 or 4 in 6% The median time to first onset for increased AST was 15 days (range: 5 days to 1.5 years) and increased ALT was 22 days (range: 7 days to 1.7 years).

Monitor AST and ALT prior to initiating pralsetinib, every 2 weeks during the first 3 months, then monthly thereafter and as clinically indicated. Withhold, reduce dose or permanently discontinue pralsetinib based on severity.

Hemorrhagic Events

Serious, including fatal, hemorrhagic events can occur with pralsetinib. Grade ≥ 3 hemorrhagic events occurred in 2.5% of patients treated with pralsetinib including one patient with a fatal hemorrhagic event.

Permanently discontinue pralsetinib in patients with severe or life-threatening hemorrhage.

Risk of Impaired Wound Healing

Impaired wound healing can occur in patients who receive drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. Therefore, pralsetinib has the potential to adversely affect wound healing.

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. The safety of resumption of pralsetinib after resolution of wound healing complications has not been established.

Embryo-fetal Toxicity

Based on findings from animal studies and its mechanism of action, pralsetinib can cause fetal harm when administered to a pregnant woman. Oral administration of pralsetinib to pregnant rats during the period of organogenesis resulted in malformations and embryolethality at maternal exposures below the human exposure at the clinical dose of 400 mg once daily.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with pralsetinib and for 2 weeks after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with pralsetinib and for 1 week after the final dose.

Specific Populations

Pregnancy

Risk Summary: Based on findings from animal studies and its mechanism of action, pralsetinib can cause fetal harm when administered to a pregnant woman There are no available data on pralsetinib use in pregnant women to inform drug-associated risk. Oral administration of pralsetinib to pregnant rats during the period of organogenesis resulted in malformations and embryolethality at maternal exposures below the human exposure at the clinical dose of 400 mg once daily Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Animal Data: In an embryo-fetal development study, once daily oral administration of pralsetinib to pregnant rats during the period of organogenesis resulted in 100% post-implantation loss at dose levels ≥20 mg/kg (approximately 1.5-2.2 times the human exposure based on area under the curve [AUC] at the clinical dose of 400 mg). Post-implantation loss also occurred at the 10 mg/kg dose level (approximately 0.5 times the human exposure based on AUC at the clinical dose of 400 mg). Once daily oral administration of pralsetinib at dose levels ≥5 mg/kg (approximately 0.2 times the human AUC at the clinical dose of 400 mg) resulted in an increase in visceral malformations and variations (absent or small kidney and ureter, absent uterine horn, malpositioned kidney or testis, retroesophageal aortic arch) and skeletal malformations and variations (vertebral and rib anomalies and reduced ossification).

Lactation

Risk Summary: There are no data on the presence of pralsetinib or its metabolites in human milk or their effects on either the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with pralsetinib and for 1 week after the final dose.

Females and Males of Reproductive Potential

Based on animal data, pralsetinib can cause embryolethality and malformations at doses resulting in exposures below the human exposure at the clinical dose of 400 mg daily.

Verify pregnancy status of females of reproductive potential prior to initiating pralsetinib.

Pralsetinib can cause fetal harm when administered to a pregnant woman.

Advise females of reproductive potential to use effective non-hormonal contraception during treatment with pralsetinib and for 2 weeks after the final dose. Pralsetinib may render hormonal contraceptives ineffective.

Advise males with female partners of reproductive potential to use effective contraception during treatment with pralsetinib and for 1 week after the final dose.

Based on histopathological findings in the reproductive tissues of male and female rats and a dedicated fertility study in which animals of both sexes were treated and mated to each other, pralsetinib may impair fertility.

Pediatric Use

The safety and effectiveness of pralsetinib have not been established in pediatric patients.

In a 4-week repeat-dose toxicology study in non-human primates, physeal dysplasia in the femur occurred at doses resulting in exposures similar to the human exposure (AUC) at the clinical dose of 400 mg. In rats there were findings of increased physeal thickness in the femur and sternum as well as tooth (incisor) abnormalities (fractures, dentin matrix alteration, ameloblast/odontoblast degeneration, necrosis) in both 4- and 13-week studies at doses resulting in exposures similar to the human exposure (AUC) at the clinical dose of 400 mg. Recovery was not assessed in the 13-week toxicology study, but increased physeal thickness in the femur and incisor degeneration did not show evidence of complete recovery in the 28-day rat study.

Geriatric Use

Of the 438 patients in ARROW who received the recommended dose of pralsetinib at 400 mg once daily, 30% were 65 years or older. No overall differences in pharmacokinetics (PK), safety or efficacy were observed in comparison with younger patients.

Hepatic Impairment

Pralsetinib has not been studied in patients with moderate hepatic impairment (total bilirubin >1.5 to 3.0 × upper limit of normal [ULN] and any aspartate aminotransferase [AST]) or severe hepatic impairment (total bilirubin >3.0 × ULN and any AST). No dose adjustment is required for patients with mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN or total bilirubin > 1 to 1.5 times ULN and any AST).

Common Adverse Effects

The most common adverse reactions (≥25%) were fatigue, constipation, musculoskeletal pain, and hypertension. The most common Grade 3-4 laboratory abnormalities (≥2 %) were decreased lymphocytes, decreased neutrophils, decreased phosphate, decreased hemoglobin, decreased sodium, decreased calcium (corrected), and increased alanine aminotransferase (ALT).

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

  • Strong CYP3A inhibitors: Avoid coadministration.

  • Combined P-gp and Strong CYP3A inhibitors: Avoid coadministration. If coadministration cannot be avoided, reduce the dose of pralsetinib.

  • Strong CYP3A inducers: Avoid coadministration. If coadministration cannot be avoided, increase the dose of pralsetinib.

Actions

Mechanism of Action

Pralsetinib is a kinase inhibitor of wild-type RET and oncogenic RET fusions (CCDC6-RET) and mutations (RET V804L, RET V804M and RET M918T) with half maximal inhibitory concentrations (IC50s) less than 0.5 nM. In purified enzyme assays, pralsetinib inhibited DDR1, TRKC, FLT3, JAK1-2, TRKA, VEGFR2, PDGFRb, and FGFR1 at higher concentrations that were still clinically achievable at Cmax. In cellular assays, pralsetinib inhibited RET at approximately 14-, 40-, and 12-fold lower concentrations than VEGFR2, FGFR2, and JAK2, respectively.

Certain RET fusion proteins and activating point mutations can drive tumorigenic potential through hyperactivation of downstream signaling pathways leading to uncontrolled cell proliferation. Pralsetinib exhibited anti-tumor activity in cultured cells and animal tumor implantation models harboring oncogenic RET fusions or mutations including KIF5B-RET, CCDC6-RET, RET M918T, RET C634W, RET V804E, RET V804L and RET V804M. In addition, pralsetinib prolonged survival in mice implanted intracranially with tumor models expressing KIF5B-RET or CCDC6- RET.

Advice to Patients

Advise the patient to read the FDA-approved patient labeling (Patient Information).

ILD/Pneumonitis

Advise patients to contact their healthcare provider if they experience new or worsening respiratory symptoms.

Hypertension

Advise patients that they will require regular blood pressure monitoring and to contact their healthcare provider if they experience symptoms of increased blood pressure or elevated readings.

Hepatotoxicity

Advise patients that hepatotoxicity can occur and to immediately contact their healthcare provider for signs or symptoms of hepatotoxicity.

Hemorrhagic Events

Advise patients that pralsetinib may increase the risk for bleeding and to contact their healthcare provider if they experience any signs or symptoms of bleeding.

Risk of Impaired Wound Healing

Advise patients that pralsetinib may impair wound healing. Advise patients that temporary interruption of pralsetinib is recommended prior to any elective surgery.

Embryo-Fetal Toxicity

Advise females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy.

Advise females of reproductive potential to use effective non-hormonal contraception during the treatment with pralsetinib and for 2 weeks after the final dose.

Advise males with female partners of reproductive potential to use effective contraception during treatment with pralsetinib and for 1 week after the final dose.

Lactation

Advise women not to breastfeed during treatment with pralsetinib and for 1 week after the final dose.

Infertility

Advise males and females of reproductive potential that pralsetinib may impair fertility.

Drug Interactions

Advise patients and caregivers to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products.

Administration

Advise patients to take pralsetinib on an empty stomach, at least 1 hour before and at least 2 hours after a meal.

Additional Information

AHFSfirstRelease. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Pralsetinib

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsule

100 mg

Gavreto

Blueprint Medicines Corporation

AHFS Drug Information. © Copyright 2021, Selected Revisions September 21, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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