Dosing & Uses
Dosage Forms & Strengths
tablet
- 100mg
- 200mg
- 300mg
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
Dosage Modifications
Dosage modifications for adverse reactions
- First dose reduction: 200 mg qDay
- Second dose reduction: 100 mg qDay
- Permanently discontinue in patients who are unable to tolerate a 100-mg dose
Intracranial hemorrhage
- First occurrence of Grade 1 or 2: Withhold until resolution; resume at reduced dose
- Subsequent occurrence of Grade 1 or 2: Permanently discontinue
- Grade 3 or 4: Permanently discontinue
CNS effects
- Grade 1: Continue dose at the same dose or withhold until improvement to baseline or resolution; resume at same dose or reduced dose
- Grade 2 or 3: Withhold until improvement to baseline, Grade 1, or resolution; resume at same dose or reduced dose
- Grade 4: Permanently discontinue
Other adverse reactions
- Grade 3 or 4: Withhold until improvement to Grade ≤2, or resolution; resume at same dose or reduced dose, as clinically appropriate
Concomitant use of strong or moderate CYP3A4 inhibitors
- Strong or moderate CYP3A4 inhibitors: Avoid use; if concomitant use with a moderate CYP3A inhibitor is unavoidable, reduce starting dose of avapritinib to 100 mg qDay
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
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
Dosing Considerations
Select patients for treatment based on the presence of a PDGFRA exon 18 mutation
An FDA-approved test for the detection of exon 18 mutations is not currently available
Safety and efficacy not established
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Adverse Effects
>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%)
Warnings
Contraindications
None
Cautions
Intracranial hemorrhage (eg, subdural hematoma, intracranial hemorrhage, cerebral hemorrhage) occurred
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
Drug interaction overview
- Avapritinib is a CYP3A4 and a CYP2C9 substrate
-
Strong and moderate CYP3A inhibitors
- Coadministration with a strong or moderate CYP3A inhibitor increases avapritinib plasma concentrations, which may increase the incidence and severity of adverse reactions of avapritinib
-
Strong and moderate CYP3A inducers
- Coadministration with a strong or moderate CYP3A inducer decreases avapritinib plasma concentrations, which may decrease efficacy of avapritinib
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
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
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
Absorption
Peak plasma concentration: 813 ng/mL
Peak plasma time: 2-4 hr
AUC: 15400 hr⋅ng/mL
Steady-state was reached by day 15
Effects of food
- Peak plasma concentration increased by 59% and AUC increased by 29% when administered with a high-calorie, high-fat meal (~909 calories, 58 grams carbohydrate, 56 grams fat, and 43 grams protein) compared with the fasted state
Distribution
Vd: 1200 L
Blood-to-plasma ratio: 0.95
Metabolism
Primarily metabolized by CYP3A4 and to a lesser extent by CYP2C9 into unchanged drug and its metabolites M690 (hydroxy glucuronide) and M499 (oxidative deamination)
Following oral administration of 300-mg dose, the steady-state AUC of M499 is ~80% of the AUC of avapritinib
M499 is not likely to contribute to efficacy at the recommended dose of avapritinib
Elimination
Half-life: 32-57 hr
Excretion
- Feces (70% [11% unchanged])
- Urine (18% [0.23% unchanged])
Administration
Oral Administration
Administer on an empty stomach, at least 1 hr before and 2 hr after a meal
Missed dose
- Do not make up for a missed dose within 8 hr of the next scheduled dose
- Do not take an additional dose if vomiting occurs after administration; continue with the next scheduled dose
Storage
Store at 20-25ºC (68-77ºF); excursions are permitted to 15-30ºC (59-86ºF)
Images
Patient Handout
Formulary
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