Skip to Content

Avapritinib

Class: Antineoplastic Agents
Chemical Name: (1S)-1-(4-fluorophenyl)-1-[2-[4-[6-(1-methylpyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]piperazin-1-yl]pyrimidin-5-yl]ethanamine
Molecular Formula: C26H27FN10
CAS Number: 1703793-34-3
Brands: Ayvakit

Medically reviewed by Drugs.com. Last updated on Feb 17, 2020.

Introduction

Avapritinib is an antineoplastic agent.

Uses for Avapritinib

Avapritinib has the following uses:

Avapritinib is a kinase inhibitor indicated for the treatment of adults with unresectable or metastatic gastrointestinal stromal tumor (GIST) harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation, including PDGFRA D842V mutations.1

Avapritinib Dosage and Administration

General

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

Tablets: 100 mg, 200 mg and 300 mg.1

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 avapritinib based on the presence of a PDGFRA exon 18 mutation.1

  • The recommended dosage of avapritinib is 300 mg orally once daily on an empty stomach, at least one hour before and two hours after a meal.1

Cautions for Avapritinib

Contraindications

None.1

Warnings/Precautions

Intracranial Hemorrhage

Intracranial hemorrhage (e.g., subdural hematoma, intracranial hemorrhage, cerebral hemorrhage) occurred in 1% of the 267 patients with GIST and overall in 3% of the 335 patients who received avapritinib. Events of intracranial hemorrhage occurred in a range from 1.7 months to 19.3 months after initiating avapritinib. Overall, 0.9% of patients receiving avapritinib required permanent discontinuation for an intracranial hemorrhage; 1.2% required dosage interruption followed by dose reduction.1

Withhold avapritinib and then resume at a reduced dose upon resolution, or permanently discontinue avapritinib based on severity.1

Central Nervous System Effects

A broad spectrum of central nervous system (CNS) adverse reactions can occur in patients receiving avapritinib. These include cognitive impairment, dizziness, sleep disorders, mood disorders, speech disorders, and hallucinations. CNS adverse reactions overall occurred in 58% of 335 patients who received avapritinib. Cognitive impairment occurred in 41% of the 335 patients who received avapritinib; 3.6% of these were severe (Grade 3 or 4). Dizziness occurred in 20% of patients; 0.6% of these events were severe. Sleep disorders occurred in 15% of patients; 0.3% of these events were severe. Mood disorders occurred in 13% of patients; 1.5% of these events were severe. Speech disorders occurred in 6% of patients; none of these events were severe. Hallucinations occurred in 2.1% of patients; none of these events were severe. The median time to onset of the first CNS adverse reaction was 6.1 weeks (range 1 day to 1.9 years). Overall, 3.9% of patients required permanent discontinuation of avapritinib for a CNS adverse reaction, 17% required a dosage interruption, and 10% required dose reduction.1

Depending on the severity, withhold avapritinib and then resume at the same dose or at a reduced dose upon improvement, or permanently discontinue avapritinib.1

Embryo-fetal Toxicity

Based on findings from animal studies and its mechanism of action, avapritinib can cause fetal harm when administered to pregnant women. Oral administration of avapritinib during the period of organogenesis was teratogenic and embryotoxic in rats at exposures approximately 2.7 times the human exposure based on area under the curve (AUC) at the 300 mg dose. Advise pregnant women of the potential risk to a fetus. Advise females and males of reproductive potential to use effective contraception during treatment with avapritinib and for 6 weeks after the final dose.1

Specific Populations

Pregnancy

Risk Summary: Based on findings from animal studies and its mechanism of action, avapritinib can cause fetal harm when administered to a pregnant woman. There are no available data on avapritinib use in pregnant women. Oral administration of avapritinib to pregnant animals during the period of organogenesis was teratogenic and embryotoxic in rats at exposure levels approximately 2.7 times the human exposure based on AUC at the 300 mg dose. Advise pregnant women of the potential risk to a fetus.1

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.1

Animal Data: In a reproductive toxicity study, administration of avapritinib to rats during the period of organogenesis resulted in decreased fetal body weights, post-implantation loss, and increases in visceral (hydrocephaly, septal defect, and stenosis of the pulmonary trunk) and skeletal (sternum) malformations at doses greater than or equal to 10 mg/kg/day (approximately 2.7 times the human exposure based on AUC at the 300 mg dose).1

Lactation

Risk Summary: There are no data on the presence of avapritinib or its metabolites in human milk or the effects of avapritinib on the breastfed child or milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with avapritinib and for 2 weeks following the final dose.1

Females and Males of Reproductive Potential

Verify the pregnancy status of females of reproductive potential prior to initiating avapritinib.1

Avapritinib can cause fetal harm when administered to pregnant women. 1

Advise females of reproductive potential to use effective contraception during treatment with avapritinib and for 6 weeks after the final dose.1

Advise males with female partners of reproductive potential to use effective contraception during treatment with avapritinib and for 6 weeks after the final dose.1

Based on findings from animal studies, avapritinib may impair both male and female fertility.1

Pediatric Use

The safety and effectiveness of avapritinib in pediatric patients have not been established.1

Geriatric Use

Of the 204 patients who received avapritinib in NAVIGATOR, 40% were 65 years or older, while 6% were 75 years and older. No overall differences in safety or efficacy were observed between these patients and younger adult patients.1

Renal Impairment

No dose adjustment is recommended for patients with mild or moderate renal impairment [creatinine clearance (CLcr) 30 to 89 mL/min estimated by Cockcroft-Gault]. The recommended dose of avapritinib has not been established for patients with severe renal impairment (CLcr 15 to 29 mL/min) or end-stage renal disease (CLcr <15 mL/min).1

Hepatic Impairment

No dose adjustment is recommended for patients with mild [total bilirubin ≤ upper limit of normal [ULN] and aspartate aminotransferase (AST) > ULN or total bilirubin > 1 to 1.5 times ULN and any AST] or moderate (total bilirubin >1.5 to 3 times ULN and any AST) hepatic impairment. The recommended dose of avapritinib has not been established for patients with severe hepatic impairment.1

Common Adverse Effects

The most common adverse reactions (incidence ≥ 20%) are edema, nausea, fatigue/asthenia, cognitive impairment, vomiting, decreased appetite, diarrhea, hair color changes, increased lacrimation, abdominal pain, constipation, rash and dizziness.1

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 and Moderate CYP3A Inhibitors: Avoid coadministration of avapritinib with strong and moderate CYP3A inhibitors. If coadministration of avapritinib with a moderate inhibitor cannot be avoided, reduce dose of avapritinib.1

  • Strong and Moderate CYP3A Inducers: Avoid coadministration of avapritinib with strong and moderate CYP3A inducers.1

Actions

Mechanism of Action

Avapritinib is a tyrosine kinase inhibitor that targets PDGFRA and PDGFRA D842 mutants as well as multiple KIT exon 11, 11/17 and 17 mutants with half maximal inhibitory concentrations (IC50s) less than 25 nM. Certain mutations in PDGFRA and KIT can result in the autophosphorylation and constitutive activation of these receptors which can contribute to tumor cell proliferation. Other potential targets for avapritinib include wild type KIT, PDGFRB, and CSFR1.1

In in vitro cellular assays, avapritinib inhibited the autophosphorylation of KIT D816V and PDGFRA D842V, mutants associated with resistance to approved kinase inhibitors, with IC50 of 4 nM and 30 nM, respectively. Avapritinib also had anti-tumor activity in mice implanted with an imatinib-resistant patient-derived xenograft model of human GIST with activating KIT exon 11/17 mutations.1

Advice to Patients

Advise the patient to read the FDA-approved patient labeling (Patient Information).1

Intracranial Hemorrhage

Advise patients to contact their healthcare provider immediately if experiencing neurological signs and symptoms that may be associated with intracranial hemorrhage.1

Central Nervous System Effects

Advise patients and caretakers to notify their healthcare provider if they experience new or worsening CNS symptoms. Advise patients not to drive or operate hazardous machinery if they are experiencing CNS adverse reactions.1

Embryo-Fetal Toxicity

Advise pregnant women and 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.1

Advise females of reproductive potential to use effective contraception during treatment with avapritinib and for 6 weeks after the final dose. 1

Advise males with female partners of reproductive potential to use effective contraception during treatment with avapritinib and for 6 weeks after the final dose.1

Lactation

Advise women not to breastfeed during treatment with avapritinib and for 2 weeks following the final dose.1

Infertility

Advise females and males of reproductive potential that avapritinib may impair fertility. 1

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.1

Administration

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

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.

Avapritinib

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablet, Film Coated

100 mg

Ayvakit

Blueprint Medicines Corporation

200 mg

Ayvakit

Blueprint Medicines Corporation

300 mg

Ayvakit

Blueprint Medicines Corporation

AHFS Drug Information. © Copyright 2020, Selected Revisions February 17, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Blueprint Medicines Corporation. Ayvakit (avapritinib) tablets, for oral use prescribing information. 2020 Jan. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=645c887c-8cd4-4623-8da9-ac223d71a8b9