Avapritinib

Indications

Avapritinib is used for: Gastrointestinal Stromal Tumors

Adult Dose

Gastrointestinal Stromal Tumors Indicated for adults with unresectable or metastatic gastrointestinal stromal tumor (GIST) harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation, including PDGFRA D842V mutation 300 mg PO qDay Continue until disease progression or unacceptable toxicity Hepatic impairment Mild-to-moderate (total bilirubin ?3x ULN and any AST): No dosage adjustment necessary Severe (total bilirubin >3x ULN and any AST): Recommended dose has not been established

Child Dose

Renal Dose

Renal impairment Mild-to-moderate (CrCl 30 to 90 mL/mL): No dosage adjustment necessary Severe or end-stage renal disease (CrCl <30 mL/min): Recommended dose has not been established

Administration

Administer on an empty stomach, at least 1 hr before and 2 hr after a meal

Contra Indications

Precautions

A broad spectrum of CNS adverse reactions were reported; these include cognitive impairment, dizziness, sleep disorders, mood disorders, speech disorders, and hallucinations Based on findings from animal studies and its mechanism of action, fetal harm can occur when administered to pregnant women Intracranial hemorrhage (eg, subdural hematoma, intracranial hemorrhage, cerebral hemorrhage) occurred

Pregnancy-Lactation

Pregnancy Based on findings from animal studies and its mechanism of action, fetal harm may occur when administered to a pregnant woman No data available on use in pregnant women Verify pregnancy status of females of reproductive potential before initiation Contraception Females of reproductive potential: Use effective contraception during treatment and for 6 weeks after the final dose Males with female partners of reproductive potential: Use effective contraception during treatment and for 6 weeks after the final dose Infertility Based on findings from animal studies, may impair fertility for both males and females Animal studies H4 Oral administration of avapritinib to pregnant animals during organogenesis was teratogenic and embryotoxic in rats at exposure levels ~2.7 times the human exposure based on AUC at the 300-mg dose Advise pregnant women of the potential risk to a fetus Lactation 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 Advise women not to breastfeed during treatment and for 2 weeks following the final dose

Interactions

Adverse Effects

Side effects of Avapritinib : >10% All grades Decreased hemoglobin (81%) Edema (72%) Increased bilirubin (69%) Nausea (64%) Decreased leukocytes (62%) Fatigue (61%) Increased AST (51%) Decreased phosphate (49%) Cognitive impairment (48%) Decreased neutrophils (43%) Vomiting (38%) Decreased appetite (38%) Diarrhea (37%) Decreased potassium (34%) Increased lacrimation (33%) Abdominal pain (31%) Decreased albumin (31%) Decreased magnesium (29%) Increased creatinine (29%) Decreased sodium (28%) Decreased platelets (27%) Increased INR (24%) Constipation (23%) Rash (23%) Dizziness (22%) Hair color changes (21%) Increased ALT (19%) Headache (17%) Dyspnea (17%) Sleep disorders (16%) Taste effects (15%) Pyrexia (14%) Increased alkaline phosphatase (14%) Mood disorders (13%) Alopecia (13%) Decreased weight (13%) Increased activated partial thromboplastin time (13%) Pleural effusion (12%) Grade >3 Decreased hemoglobin (28%) Decreased phosphate (13%) 1-10% All grades Hypertension (8%) Thyroid disorders (hyperthyroid, hypothyroid) (3%) Palmar-plantar erythrodysesthesia (1%) Grade>3 Fatigue (9%) Increased bilirubin (9%) Abdominal pain (6%) Decreased neutrophils (6%) Decreased potassium (6%) Decreased sodium (7%) Decreased leukocytes (5%) Diarrhea (4.9%) Cognitive impairment (4.9%) Decreased appetite (2.9%) Nausea (2.5%) Dyspnea (2.5%) Rash (2.1%) Vomiting (2%) Edema (2%) Pleural effusion (2%) Decreased albumin (2%) Constipation (1.5%) Increased AST (1.5%) Mood disorders (1%) Decreased weight (1%) Decreased magnesium (1%) Increased alkaline phosphatase (1%) <1% Grade >3 Increased INR (0.6%) Pyrexia (0.5%) Dizziness (0.5%) Headache (0.5%) Hair color changes (0.5%) Decreased platelets (0.5%) Increased ALT (0.5%)

Mechanism of Action

Tyrosine kinase inhibitor binds to and inhibits specific mutant forms of PDGFRα and c-Kit, including the PDGFRα D842V mutant and various KIT exon 17 mutants This results in the inhibition of PDGFRa- and c-Kit-mediated signal transduction pathways and the inhibition of proliferation in tumor cells that express these PDGFRa and c-Kit mutants