Dosing & Uses
Dosage Forms & Strengths
tablet
- 25mg
- 50mg
- 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
Systemic Mastocytosis
Indicated for advanced systemic mastocytosis (AdvSM)
AdvSM includes patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematological neoplasm (SMAHN), and mast cell leukemia (MCL)
200 mg PO qDay
Continue until disease progression or unacceptable toxicity
Dosage Modifications
Dose reductions for adverse reactions
-
GIST
- First dose reduction: 200 mg qDay
- Second dose reduction: 100 mg qDay
- Unable to tolerate a 100-mg dose: Permanently discontinue
-
AdvSM
- First dose reduction: 100 mg qDay
- Second dose reduction: 50 mg qDay
- Third dose reduction: 25 mg qDay
- Unable to tolerate a 25-mg dose: Permanently discontinue
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
Thrombocytopenia
- Platelet counts <50 x 109/L: Interrupt until platelet count ≥50 x 109/L, then resume at reduced dose
- If platelet counts do not recover above 50 x 109/L, consider platelet support
Strong or moderate CYP3A4 inhibitors
- Avoid coadministration
-
If use is unavoidable, reduce starting dose as follows
- GIST: 100 mg PO qDay
- AdvSM: 50 mg PO qDay
Renal impairment
- Mild-to-moderate (CrCl 30-90 mL/mL): No dosage adjustment necessary
- Severe or end-stage renal disease (CrCl <30 mL/min): Effect on pharmacokinetics unknown
Hepatic impairment
- Mild-to-moderate (total bilirubin ≤3x ULN and any AST): No dosage adjustment necessary
- Severe (total bilirubin >3x ULN and any AST): Effect on pharmacokinetics unknown
Dosing Considerations
Verify pregnancy status in females of reproductive potential
Patient selection (GIST)
- Select patients based on presence of a PDGFRA exon 18 mutation
- No FDA-approved test available
Limitations of use
- Not recommended for AdvSM with platelet counts <50 X 109/L
Safety and efficacy not established
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Adverse Effects
>10%
-
All grades
-
GIST
- 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 (aPTT) (13%)
- Pleural effusion (12%)
-
AdvSM
- Edema (79%)
- Decreased platelets (64%)
- Decreased hemoglobin (55%)
- Decreased neutrophils (54%)
- Decreased calcium (50%)
- Increased bilirubin (41%)
- Increased AST (38%)
- Decreased lymphocytes (34%)
- Diarrhea (28%)
- Decreased potassium (26%)
- Nausea (24%)
- Increased alkaline phosphatase (24%)
- Fatigue/asthenia (23%)
- Increased creatinine (20%)
- Vomiting (18%)
- Increased ALT (18%)
- Decreased sodium (18%)
- Headache (15%)
- Decreased albumin (15%)
- Cognitive effects (14%)
- Abdominal pain (14%)
- Increased aPTT (14%)
- Decreased magnesium (14%)
- Taste effects (13%)
- Dizziness (13%)
- Constipation (11%)
- Epistaxis (11%)
- Increased potassium (11%)
Grade ≥3
-
GIST
- Decreased hemoglobin (28%)
- Decreased phosphate (13%)
-
AdvSM
- Decreased neutrophils (25%)
- Decreased hemoglobin (23%)
- Decreased platelets (21%)
- Decreased lymphocytes (11%)
1-10%
All grades
-
GIST
- Hypertension (8%)
- Thyroid disorders (hyperthyroid, hypothyroid) (3%)
- Palmar-plantar erythrodysesthesia (1%)
-
AdvSM
- Arthralgia (10%)
- Increased lymphocytes (10%)
- Dyspnea (9%)
- Alopecia (9%)
- Lacrimation increased (9%)
- Decreased phosphate (9%)
- Rash (8%)
- Pruritus (8%)
- Decreased appetite (8%)
- Upper respiratory tract infection (6%)
- Urinary tract infection (6%)
- Insomnia (6%)
- Pain in extremity (6%)
- Hair color changes (6%)
- Ascites (5%)
- Anemia (5%)
- Subdural hematoma (4%)
- Flushing (3.8%)
- Hypertension (3.8%)
- Hypotension (3.8%)
- Pleural effusion (3%)
- Pneumonia (3%)
- Herpes zoster (2.5%)
- Cardiac failure (2.5%)
- Hot flush (2.5%)
- Cough (2.5%)
- Acute kidney injury (2%)
- Gastrointestinal hemorrhage (2%)
- Intracranial hemorrhage (2%)
- Encephalopathy (2%)
- Gastric hemorrhage (2%)
- Pyrexia (2%)
- Cardiac failure congestive (1.3%)
- Gastrointestinal hemorrhage (1.3%)
- Large intestine perforation (1.3%)
- Cholelithiasis (1.3%)
Grade ≥3
GIST
- 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%)
AdvSM
- Edema (5%)
- Increased alkaline phosphatase (5%)
- Fatigue/asthenia (4%)
- Decreased potassium (4%)
- Vomiting (3%)
- Decreased calcium (3%)
- Increased bilirubin (3%)
- Diarrhea (1%)
- Nausea (1%)
- Abdominal pain (1%)
- Cognitive effects (1%)
- Arthralgia (1%)
- Increased aPTT (1%)
- Increased AST (1%)
- Increased ALT (1%)
- Decreased sodium (1%)
- Decreased albumin (1%)
- Decreased magnesium (1%)
<1%
Grade ≥3
-
GIST
- 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
A broad spectrum of CNS adverse reactions reported; these include, dizziness, sleep disorders, mood disorders, speech disorders, and hallucinations
Cognitive adverse reactions reported; depending on severity, withhold treatment and then resume at same dose or at a reduced dose upon improvement, or permanently discontinue treatment
Fetal harm can occur when administered to pregnant females
Intracranial hemorrhage
- Intracranial hemorrhage (eg, subdural hematoma, intracranial hemorrhage, cerebral hemorrhage) occurred; thrombocytopenia was generally reversible by dose reduction or interruption
- Monitor patients closely for the risk of intracranial hemorrhage including those with thrombocytopenia, vascular aneurysm or a history of intracranial hemorrhage or cerebrovascular accident within the prior year
- Permanently discontinue therapy if intracranial hemorrhage of any grade occurs
Advanced systemic mastocytosis
- Platelet count must be performed prior to initiating therapy; drug not recommended in patients with AdvSM with platelet counts < 50 X 109/L
- Following treatment initiation, platelet counts must be performed every 2 weeks for first 8 weeks regardless of baseline platelet count
- After 8 weeks of treatment, monitor platelet counts every 2 weeks (or more frequently as clinically indicated) if values are less than 75 X 109/L, every 4 weeks if values are between 75 and 100 X 109/L, and as clinically indicated if values are greater than 100 X 109/L
- Manage platelet counts of < 50 X 109/L by treatment interruption or dose-reduction; platelet support may be necessary
- Dose-interruptions and dose reductions for thrombocytopenia occurred in 20% and 22% of treated patients, respectively; thrombocytopenia was generally reversible by reducing or interrupting drug
Drug interaction overview
Substrate of CYP3A4 and CYP2C9
Strong and moderate CYP3A inhibitors
- Avoid coadministration; reduce dose if unable to avoid
- Strong or moderate CYP3A inhibitor increases avapritinib plasma concentrations and adverse reactions
Strong and moderate CYP3A inducers
- Avoid coadministration
- Strong or moderate CYP3A inducer decreases plasma concentrations and 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
- Oral administration of avapritinib to pregnant animals during organogenesis was teratogenic and embryotoxic in rats at exposure levels approximately 6.3 and 2.7 times the human exposure based on AUC at the 200 mg and 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 time: 2-4 hr
Steady-state reached by day 15
Peak plasma concentration
- AdvSM: 377 ng/mL
- GIST: 813 ng/mL
AUC
- AdvSM: 6,600 ng·hr/mL
- GIST: 15,400 ng·hr/mL
Accumulation ratio
- AdvSM: 6.41
- GIST: 3.82
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
Blood-to-plasma ratio: 0.95
Protein bound: 98.8%
Vd
- GIST: 1,200 L
- AdvSM: 1,900 L
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
- GIST: 32-57 hr
- AdvSM: 20-39 hr
Clearance
- GIST: 21.8 L/hr
- AdvSM: 40.3 L/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)
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Patient Handout
Formulary
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