Avapritinib is a tyrosine kinase inhibitor that targets KIT D816V and platelet-derived growth factor receptor alpha (PDGFRA) mutations as well as multiple KIT exon 11, 11/17, and 17 mutations. It is indicated in adults with unresectable or metastatic gastrointestinal stromal tumor (GIST) harboring a PDGFRA exon 18 mutation, including PDGFRA D842V mutations. Avapritinib is also indicated in adults with advanced systemic mastocytosis (AdvSM) including aggressive systemic mastocytosis, systemic mastocytosis with associated hematological neoplasm, and mast cell leukemia and adults with indolent systemic mastocytosis (ISM). Use is not recommended in patients with AdvSM or ISM who have platelet counts less than 50 x 109 cell/L. Intracranial hemorrhage and cognitive effects have been reported with avapritinib therapy.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Emetic Risk
-Moderate/High
-Administer routine antiemetic prophylaxis prior to treatment.
Route-Specific Administration
Oral Administration
-Avapritinib must be given orally on an empty stomach, 1 hour before or 2 hours after the ingestion of food.
-If a dose is missed, do not make it up if the next dose is due within 8 hours.
-If vomiting occurs, do not administer an additional dose of avapritinib; continue regular administration with the next scheduled dose.
Cognitive adverse reactions occurred in 33% of patients with gastrointestinal stromal tumor (GIST), advanced systemic mastocytosis (AdvSM), or indolent systemic mastocytosis (ISM) who received avapritinib (30 to 600 mg/day) in a pooled analysis of 5 clinical trials (n = 995). Therapy interruption, dose reduction, or discontinuation may be necessary in patients who develop cognitive effects. Cognitive effects (41%; grade 3 or higher, 5%) including memory impairment (21%; grade 3, less than 1%), cognitive disorder/impaired cognition (12%; grade 3, 1.2%), confusion/confusional state (6%; grade 3, less than 1%), amnesia (3%; grade 3, less than 1%), somnolence/drowsiness (2%), and speech disorder/dysarthria (2%) occurred in patients with GIST who received avapritinib in clinical trials (n = 601). Additionally, cognitive adverse reactions (28%; grade 3 or higher, 3%) including memory impairment (16%), impaired cognition (10%; grade 3, less than 1%), and confusion (6%; grade 3, less than 1%) were reported in patients with AdvSM who received avapritinib in clinical trials (n = 148). Cognitive adverse reactions occurred in 7.8% (grade 3, less than 1%) of patients with ISM who received avapritinib plus best supportive care (n = 246) in a randomized trial. In ISM patients, the median time to onset of the first cognitive adverse reaction was 2.3 (range, 0 to 5.4 months) months and the median time to improvement to grade 1 or less was 2.1 (range. 0.4 to 2.1) months. The median times to onset of the first cognitive adverse reaction were 8.4 weeks (range, 1 day to 4 years) in patients with GIST and 13.3 weeks (range, 1 day to 1.8 years) in patients with AdvSM. In patients with GIST or AdvSM who developed grade 2 or higher adverse events, the median times to resolution to grade 1 or less were 7.9 weeks and 8.1 weeks in patients with GIST or AdvSM, respectively. Cognitive impairment occurred in 48% (grade 3 or 4, 4.9%) of patients with unresectable or metastatic GIST who received avapritinib 300 or 400 mg/day in a multicenter, noncomparative trial (n = 204). Cognitive impairment included memory impairment, cognitive disorder, confusional state, disturbance in attention, amnesia, mental impairment, mental status changes, encephalopathy, dementia, abnormal thinking, and mental disorder. Cognitive effects were reported in 14% (grade 3 or 4, 1%) of patients with AdvSM who received avapritinib 200 mg/day in 2 clinical trials (n = 80). Cognitive effects included memory impairment, cognitive disorder, confusional state, delirium, and disorientation. Serious encephalopathy occurred in 2% of avapritinib-treated AdvSM patients.
In clinical trials, dizziness occurred in 22% (grade 3 or 4, 0.5%) of patients with unresectable or metastatic gastrointestinal stromal tumor who received avapritinib 300 or 400 mg/day (n = 204), 13% of patients with advanced systemic mastocytosis who received avapritinib 200 mg/day (n = 80), and 13% of patients with indolent systemic mastocytosis who received avapritinib 25 mg/day plus best supportive care (n = 141).
Sleep disorders (e.g., insomnia and somnolence) occurred in 16% of patients with unresectable or metastatic gastrointestinal stromal tumor who received avapritinib 300 or 400 mg/day (n = 204) in a multicenter, noncomparative trial. In clinical trials, insomnia was reported in 6% of patients with advanced systemic mastocytosis who received avapritinib 200 mg/day (n = 80) and 6% of patients with indolent systemic mastocytosis who received avapritinib 25 mg/day plus best supportive care (n = 141).
Mood disorders (e.g., agitation, anxiety, depression, dysphoria, irritability, nervousness, personality change, and suicidal ideation) occurred in 13% (grade 3 or 4, 1%) of patients with unresectable or metastatic gastrointestinal stromal tumor who received avapritinib 300 or 400 mg/day (n = 204) in a multicenter, noncomparative trial.
Heart failure (2.5%) and congestive heart failure (1.3%) were reported in patients with advanced systemic mastocytosis who received avapritinib 200 mg/day in 2 clinical trials (n = 80).
Flushing (3.8%) and hot flashes/flush (2.5%) were reported in patients with advanced systemic mastocytosis who received avapritinib 200 mg/day in 2 clinical trials (n = 80). Flushing also occurred in 11% of patients with indolent systemic mastocytosis who received avapritinib 25 mg/day plus best supportive care (n = 141) in a randomized trial.
In clinical trials, taste effects (i.e., dysgeusia and/or ageusia) occurred in 15% of patients with unresectable or metastatic gastrointestinal stromal tumor who received avapritinib 300 or 400 mg/day (n = 204) and 13% of patients with advanced systemic mastocytosis who received avapritinib 200 mg/day (n = 80).
In clinical trials, headache occurred in 17% (grade 3 or 4, 0.5%) of patients with unresectable or metastatic gastrointestinal stromal tumor who received avapritinib 300 or 400 mg/day (n = 204) and 15% of patients with advanced systemic mastocytosis who received avapritinib 200 mg/day (n = 80).
Intracranial bleeding (e.g., subdural hematoma and cerebral hemorrhage) occurred in 2.9% of patients with gastrointestinal stromal tumor (GIST; n = 601) or advanced systemic mastocytosis (AdvSM; n = 148) who received avapritinib (30 to 600 mg/day) in a pooled analysis of 4 clinical trials; fatal events were reported in less than 1% of patients. No patients with indolent systemic mastocytosis (ISM) treated with avapritinib (n = 246) experienced intracranial bleeding in a clinical trial. Monitor patients closely for neurological signs or symptoms of intracranial hemorrhage. Discontinue avapritinib therapy in patients who develop an intracranial hemorrhage. Intracranial bleeding occurred in 1.1% (grade 3 or higher, 0.7%) of patients with GIST who received avapritinib in clinical trials (n = 267). The time to onset of intracranial bleeding event reactions occurred at 1.7 to 19.3 months after avapritinib was started. Additionally, intracranial bleeding (3.8%) and subdural hematoma (4%) were reported in patients with AdvSM who received avapritinib 200 mg/day in 2 clinical trials (n = 80). Hematoma (e.g., contusion and pelvic hematoma) occurred in 6% of patients with ISM who received avapritinib 25 mg/day plus best supportive care (n = 141) in a randomized trial.
Serious GI bleeding (2%) and fatal tumor hemorrhage (1%) occurred in patients with unresectable or metastatic gastrointestinal stromal tumor who received avapritinib 300 or 400 mg/day in a multicenter, noncomparative trial (n = 204). GI bleeding (1.3%), GI perforation of the large intestine (1.3%), and epistaxis (11%) were reported in patients with advanced systemic mastocytosis who received avapritinib 200 mg/day in 2 clinical trials (n = 80). Bleeding (e.g., epistaxis, gingival bleeding, hematochezia, rectal hemorrhage, retinal hemorrhage) occurred in 5% of patients with indolent systemic mastocytosis who received avapritinib 25 mg/day plus best supportive care (n = 141) in a randomized trial.
In clinical trials, edema occurred in 72% (grade 3 or 4, 2%) of patients with unresectable or metastatic gastrointestinal stromal tumor who received avapritinib 300 or 400 mg/day (n = 204) and 79% (grade 3 or 4, 5%) of patients with advanced systemic mastocytosis (AdvSM) who received avapritinib 200 mg/day (n = 80). Ascites was reported in 5% of patients with AdvSM. The term edema included face swelling, conjunctival/eye edema, blepharedema, orbital/periorbital edema, mouth edema, pharyngeal edema, peripheral edema/swelling, testicular swelling/edema. Eye edema including periorbital/orbital edema, eye swelling, eyelid edema/swelling, and eyelid ptosis (13%), peripheral edema (12%), and face edema including (7%) occurred in patients with indolent systemic mastocytosis who received avapritinib 25 mg/day plus best supportive care (n = 141) in a randomized trial.
Nausea (64%; grade 3 or 4, 2.5%), vomiting (38%; grade 3 or 4, 2%), and dyspepsia (16%) occurred in patients with unresectable or metastatic gastrointestinal stromal tumor who received avapritinib 300 or 400 mg/day in a multicenter, noncomparative trial (n = 204). Additionally, nausea (24%; grade 3 or 4, 1%) and vomiting (18%; grade 3 or 4, 3%) were reported in patients with advanced systemic mastocytosis who received avapritinib 200 mg/day in 2 clinical trials (n = 80).
Diarrhea (37%; grade 3 or 4, 4.9%), abdominal pain (31%; grade 3 or 4, 6%), and constipation (23%; grade 3 or 4, 1.5%) occurred in patients with unresectable or metastatic gastrointestinal stromal tumor who received avapritinib 300 or 400 mg/day in a multicenter, noncomparative trial (n = 204). Additionally, diarrhea (28%; grade 3 or 4, 1%), abdominal pain (14%; grade 3 or 4, 1%), and constipation (11%) were reported in patients with advanced systemic mastocytosis who received avapritinib 200 mg/day in 2 clinical trials (n = 80).
In clinical trials, anorexia/decreased appetite occurred in 38% (grade 3 or 4, 2.9%) of patients with unresectable or metastatic gastrointestinal stromal tumor (GIST) who received avapritinib 300 or 400 mg/day (n = 204) and 8% of patients with advanced systemic mastocytosis who received avapritinib 200 mg/day (n = 80). Weight loss was reported in 13% (grade 3 or 4, 1%) of patients with GIST.
In clinical trials, rash (e.g., maculopapular rash and erythematous rash/erythema) occurred in 23% (grade 3 or 4, 2.1%) of patients with unresectable or metastatic gastrointestinal stromal tumor (GIST) who received avapritinib 300 or 400 mg/day (n = 204), 8% of patients with advanced systemic mastocytosis (AdvSM) who received avapritinib 200 mg/day (n = 80), and 6% of patients with indolent systemic mastocytosis who received avapritinib 25 mg/day plus best supportive care (n = 141). Palmar-plantar erythrodysesthesia (hand and foot syndrome) was reported in 1% of patients with GIST. Pruritus occurred in 8% of patients with AdvSM.
Hair discoloration/hair color changes (21%; grade 3 or 4, 0.5%) and alopecia (13%) occurred in patients with unresectable or metastatic gastrointestinal stromal tumor who received avapritinib 300 or 400 mg/day in a multicenter, noncomparative trial (n = 204). Additionally, hair color changes (6%) and alopecia (9%) were reported in patients with advanced systemic mastocytosis who received avapritinib 200 mg/day in 2 clinical trials (n = 80).
In clinical trials, increased lacrimation occurred in 33% of patients with unresectable or metastatic gastrointestinal stromal tumor who received avapritinib 300 or 400 mg/day (n = 204) and 9% of patients with advanced systemic mastocytosis who received avapritinib 200 mg/day (n = 80).
Dyspnea (17%; grade 3 or 4, 2.5%) and pleural effusion (12%; grade 3 or 4, 2%) occurred in patients with unresectable or metastatic gastrointestinal stromal tumor who received avapritinib 300 or 400 mg/day treated with avapritinib in a multicenter, noncomparative trial (n = 204). Additionally, dyspnea (9%), cough (2.5%), and serious pleural effusion (3%) were reported in patients with advanced systemic mastocytosis who received avapritinib 200 mg/day in 2 clinical trials (n = 80).
In clinical trials, fatigue/asthenia occurred in 61% (grade 3 or 4, 9%) of patients with unresectable or metastatic gastrointestinal stromal tumor who received avapritinib 300 or 400 mg/day (n = 204) and 23% (grade 3 or 4, 4%) of patients with advanced systemic mastocytosis who received avapritinib 200 mg/day (n = 80).
Serious infection including pneumonia (3%) and fatal sepsis (1%) and fever (14%; grade 3 or 4, 0.5%) occurred in patients with unresectable or metastatic gastrointestinal stromal tumor who received avapritinib 300 or 400 mg/day in a multicenter, noncomparative trial (n = 204). Additionally, upper respiratory tract infection (6%), urinary tract infection (6%), herpes zoster (2.5%), serious pneumonia (3%), and fever (2%) were reported in patients with advanced systemic mastocytosis who received avapritinib 200 mg/day in 2 clinical trials (n = 80). Respiratory tract infection (e.g., pneumonia and bronchitis) occurred in 8% of patients with indolent systemic mastocytosis who received avapritinib 25 mg/day plus best supportive care (n = 141) in a randomized trial.
In clinical trials, hypertension occurred in 8% of patients with unresectable or metastatic gastrointestinal stromal tumor who received avapritinib 300 or 400 mg/day (n = 204) and 3.8% of patients with advanced systemic mastocytosis (AdvSM) who received avapritinib 200 mg/day (n = 80). Hypotension was reported in 3.8% of patients with AdvSM.
Thyroid disorders (hyperthyroidism and hypothyroidism) occurred in 3% of patients with unresectable or metastatic gastrointestinal stromal tumor who received avapritinib 300 or 400 mg/day in a multicenter, noncomparative trial (n = 204).
Hematologic adverse events have been reported with avapritinib therapy in clinical trials. In patients with advanced systemic mastocytosis (AdvSM), monitor platelet counts at baseline, every 2 weeks for the first 8 weeks, and then every 2 weeks (or more frequently as clinically indicated) if values are less than 75 x 109 cells/L, every 4 weeks if values are between 75 and 100 x 109 cells/L, and as clinically indicated if values are greater than 100 x 109 cells/L. Therapy interruption, dose reduction, and/or discontinuation may be necessary in patients with AdvSM who develop thrombocytopenia. Consider platelet support if platelet counts do not recover to more than 50 x 109 cells/L. Hematologic parameters that worsened from baseline including decreased hemoglobin level/anemia (81%; grade 3 or 4, 28%), decreased leukocytes/leukopenia (62%; grade 3 or 4, 5%), decreased neutrophil count/neutropenia (43%; grade 3 or 4, 6%), and decreased platelet count/thrombocytopenia (27%; grade 3 or 4, 0.5%) occurred in patients with unresectable or metastatic gastrointestinal stromal tumor who received avapritinib 300 or 400 mg/day in a multicenter, noncomparative trial (n = 204). Additionally, anemia (55%; grade 3 or 4, 23%), decreased lymphocyte count/lymphopenia (34%; grade 3 or 4, 11%), neutropenia (54%; grade 3 or 4, 25%), thrombocytopenia (64%; grade 3 or 4, 21%), and increased lymphocyte count/lymphocytosis (10%) that worsened from baseline were reported in patients with AdvSM who received avapritinib 200 mg/day in 2 clinical trials (n = 80).
Increased bilirubin level/hyperbilirubinemia (69%; grade 3 or 4, 9%) and elevated hepatic enzymes including increased AST (51%; grade 3 or 4, 1.5%), ALT (19%; grade 3 or 4, 0.5%), and alkaline phosphatase (14%; grade 3 or 4, 1%) levels that worsened from baseline occurred in patients with unresectable or metastatic gastrointestinal stromal tumor who received avapritinib 300 or 400 mg/day in a multicenter, noncomparative trial (n = 204). Additionally, hyperbilirubinemia (41%; grade 3 or 4, 3%); increased AST (38%; grade 3 or 4, 1%), ALT (18%; grade 3 or 4, 1%), and alkaline phosphatase (24%; grade 3 or 4, 5%) levels; and cholelithiasis (1.3%) were reported in patients with advanced systemic mastocytosis who received avapritinib 200 mg/day in 2 clinical trials (n = 80). Increased transaminase (6%) and alkaline phosphatase (6%) levels occurred in patients with indolent systemic mastocytosis who received avapritinib 25 mg/day plus best supportive care (n = 141) in a randomized trial.
In clinical trials, decreased albumin level/hypoalbuminemia that worsened from baseline occurred in 31% (grade 3 or 4, 2%) of patients with unresectable or metastatic gastrointestinal stromal tumor who received avapritinib 300 or 400 mg/day (n = 204) and 15% (grade 3 or 4, 1%) of patients with advanced systemic mastocytosis who received avapritinib 200 mg/day (n = 80).
In clinical trials, prolonged bleeding time including increased activated partial thromboplastin time (aPTT) from baseline occurred in 13% of patients with unresectable or metastatic gastrointestinal stromal tumor (GIST) who received avapritinib 300 or 400 mg/day (n = 204) and 14% (grade 3 or 4, 1%) of patients with advanced systemic mastocytosis who received avapritinib 200 mg/day (n = 80). Increased INR from baseline was reported in 24% (grade 3 or 4, 0.6%) of patients with GIST.
In clinical trials, nephrotoxicity, specifically serious acute kidney injury, occurred in 2% of patients with unresectable or metastatic gastrointestinal stromal tumor (GIST) who received avapritinib 300 or 400 mg/day (n = 204) and 2% of patients with advanced systemic mastocytosis (AdvSM) who received avapritinib 200 mg/day (n = 80). Additionally, increased creatinine levels from baseline were reported in 29% and 20% of avapritinib-treated patients with GIST and AdvSM, respectively.
Electrolyte abnormalities that worsened from baseline including decreased phosphate level/hypophosphatemia (49%; grade 3 or 4, 13%), decreased potassium level/hypokalemia (34%; grade 3 or 4, 6%), decreased magnesium level/hypomagnesemia (29%; grade 3 or 4, 1%), and decreased sodium level/hyponatremia (28%; grade 3 or 4, 7%) occurred in patients with unresectable or metastatic gastrointestinal stromal tumor who received avapritinib 300 or 400 mg/day in a multicenter, noncomparative trial (n = 204). Additionally, decreased calcium level/hypocalcemia (50%; grade 3 or 4, 3%), hypokalemia (26%; grade 3 or 4, 4%), hyponatremia (18%; grade 3 or 4, 1%), hypomagnesemia (14%; grade 3 or 4, 1%), increased potassium level/hyperkalemia (11%), and hypophosphatemia (9%) that worsened from baseline were reported in patients with advanced systemic mastocytosis who received avapritinib 200 mg/day in 2 clinical trials (n = 80).
Arthralgia (10%; grade 3 or 4, 1%) and extremity pain (6%) were reported in patients with advanced systemic mastocytosis who received avapritinib 200 mg/day in 2 clinical trials (n = 80).
Photosensitivity was reported in 2.5% of patients with gastrointestinal stromal tumor or advanced systemic mastocytosis who received avapritinib in a pooled safety analysis (n = 1,049). Advise patients to wear protective clothing and use broad-spectrum sunscreen during and for 1 week after therapy.
Use of avapritinib is not recommended in patients with advanced systemic mastocytosis (AdvSM) or indolent systemic mastocytosis (ISM) who have severe thrombocytopenia at baseline, defined as a platelet count less than 50 x 109 cells/L. In patient with AdvSM, monitor platelet counts at baseline, every 2 weeks for the first 8 weeks; thereafter, monitor at least every 2 weeks if platelet counts are less than 75 x 109 cells/L, every 4 weeks if platelet counts are between 75 and 100 x 109 cells/L, and as clinically indicated if platelet counts are greater than 100 x 109 cells/L. Therapy interruption, dose reduction, and/or discontinuation may be necessary in patients with AdvSM who develop thrombocytopenia. Consider platelet support if platelet counts do not recover to more than 50 x 109 cells/L.
Advise patients against driving or operating machinery if they experience cognitive adverse reaction while taking avapritinib. Additionally, therapy interruption, dose reduction, or discontinuation may be necessary in patients who develop cognitive effects.
Patients with a history of vascular aneurysm, intracranial bleeding, or cerebrovascular accident/stroke within the prior year, thrombocytopenia, or who are receiving concomitant anticoagulant therapy may be at increased risk for developing intracranial bleeding with avapritinib therapy. Monitor patients closely for signs or symptoms of intracranial hemorrhage (e.g., severe headache, vision changes, or altered mental status). Permanently discontinue avapritinib therapy in patients who develop intracranial bleeding.
Instruct patients to avoid exposure to sunlamps or other sources of ultraviolet (UV) radiation and limit sunlight (UV) exposure during and for 1 week after stopping avapritinib therapy by wearing protective clothing and using broad-spectrum sunscreen.
An initial avapritinib dosage adjustment is required in patients with severe hepatic disease/impairment (Child-Pugh class C).
Pregnancy should be avoided by patients of reproductive potential during avapritinib treatment and for 6 weeks after the last dose. Although there are no adequately controlled studies in pregnant humans, avapritinib may cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving avapritinib should be apprised of the potential hazard to the fetus. In a reproductive toxicity study, administration of avapritinib to rats during 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 approximately 6.3 and 2.7 times the human exposure at the recommended doses of 200 mg and 300 mg, respectively, based on AUC.
Due to the potential for serious adverse reactions in nursing infants from avapritinib, advise women to discontinue breast-feeding during treatment and for 2 weeks after the final dose. It is not known whether avapritinib is present in human milk, although many drugs are excreted in human milk.
Counsel patients about the reproductive risk and contraception requirements during avapritinib treatment. Avapritinib may cause fetal harm if administered during pregnancy. Patients of reproductive potential should avoid pregnancy and use effective contraception during and for 6 weeks after treatment with avapritinib. These patients should undergo pregnancy testing prior to initiation of avapritinib. Women who become pregnant while receiving avapritinib should be apprised of the potential hazard to the fetus. Due to the risk of male-mediated teratogenicity, males with female partners of reproductive potential should also use effective contraception during and for 6 weeks after treatment with avapritinib. Male and female infertility may occur with avapritinib therapy based on data from animal studies. In repeat dose toxicology studies, irreversible cystic degeneration of corpora lutea in female rats and hypospermatogenesis in male dogs were observed following a 2-month recovery period after avapritinib administration. Additionally, increased pre-implantation loss and early resorptions and decreased viable embryos in females and reduced sperm production and testicular weight in males were reported in fertility studies in rats who received avapritinib.
For the treatment of gastrointestinal stromal tumors (GIST):
NOTE: The FDA has designated avapritinib as an orphan drug for this indication.
-for the treatment of unresectable or metastatic gastrointestinal stromal tumors (GIST) with platelet-derived growth factor-alpha (PDGFRA) exon 18 mutation, including PDGFRA D842V mutations:
NOTE: Patients should be selected based on the presence of a PDGFRA exon 18 mutation. An FDA-approved test for the detection of PDGFRA exon 18 mutations is not currently available.
Oral dosage:
Adults: 300 mg orally once daily until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Treatment with avapritinib resulted in an overall response rate of 84% (complete response [CR], 7%) in GIST patients with PDGFRA exon 18 mutations other than D842V (n = 43) in a multicenter, noncomparative trial; the median duration was not reached, but 61% remained in response after 6 months. Treatment with avapritinib resulted in an overall response rate of 89% (complete response [CR], 8%) in GIST patients with PDGFRA D842V mutations (n = 38); the median duration was not reached, but 59% remained in response after 6 months.
For the treatment of systemic mastocytosis:
NOTE: The FDA has designated avapritinib as an orphan drug for the treatment of mastocytosis.
-for the treatment of advanced systemic mastocytosis (AdvSM) including aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN), and mast cell leukemia:
Oral dosage:
Adults: 200 mg orally once daily until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. The overall response rate was 57% in 53 patients with AdvSM (ASM, 100% [n = 2]; SM-AHN, 58% [n = 40]; mast cell leukemia, 45% [n = 11]) who received avapritinib up to 200 mg daily in a pooled analysis from a dose-escalation (EXPLORER) trial and a phase 2 (PATHFINDER) trial; 28% of patients had a complete remission with full or partial hematologic recovery. At a median follow-up time of 11.6 months, the median duration of response and time to response were 38.3 months and 2.1 months, respectively. In this analysis, 94% of patients had a D816V mutation; 66% of patients had received prior antineoplastic therapy and 47% of patients had received prior midostaurin therapy.
-for the treatment of indolent systemic mastocytosis (ISM):
Oral dosage:
Adults: 25 mg orally once daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. The mean change in ISM Symptom Assessment Form (ISM-SAF) total symptom score (TSS) was significantly improved in patients with indolent systemic mastocytosis with moderate to severe symptoms following at least 2 prior symptom directed therapies who received avapritinib plus best supportive care (BSC) compared with placebo plus BSC (-15.33 vs. -9.64; difference, -5.69; 95% CI, -10.16 to -1.23; p = 0.012) in a randomized (2:1), double-blind, phase 3 (PIONEER) trial (n = 212). A 50% or greater reduction in ISM-SAF TSS score was achieved in 25% of patients in the avapritinib plus BSC arm compared with 10% of patients in the placebo plus BSC arm. Additionally, efficacy results related to mast cell burden, including percentage of patients with a 50% or greater reduction in serum tryptase levels, peripheral blood KIT D816V allele fraction (or undetectable), and bone marrow mast cells (or no aggregates), were significantly improved at week 24 in patients who received avapritinib plus BSC compared with placebo plus BSC.
Therapeutic Drug Monitoring:
Dosage Adjustments for Treatment-Related Toxicity
Recommended Dose Reductions
Gastrointestinal Stromal Tumor (GIST)
First dose reduction: 200 mg PO once daily.
Second dose reduction: 100 mg PO once daily. Permanently discontinue in patients unable to tolerate 100 mg/day.
Advanced Systemic Mastocytosis (AdvSM)
First dose reduction: 100 mg PO once daily.
Second dose reduction: 50 mg PO once daily.
Third dose reduction: 25 mg PO once daily. Permanently discontinue in patients unable to tolerate 25 mg/day.
GIST or AdvSM:
Cognitive Effects
-Grade 1: Continue avapritinib therapy at the same dose, a reduced dose, or withhold until improvement. When reaction improves to baseline or resolution, resume treatment at the same dose or a reduced dose.
-Grade 2 or 3: Hold avapritinib therapy. When reaction improves to baseline, grade 1, or resolution, resume treatment at the same dose or a reduced dose.
-Grade 4: Permanently discontinue avapritinib therapy.
Intracranial Hemorrhage
-Any grade: Permanently discontinue avapritinib therapy.
Other Adverse Reactions
-Grade 3 or 4: Hold avapritinib therapy. When reaction improves to grade 2 or less, resume treatment at the same dose or a reduced dose.
AdvSM:
Thrombocytopenia
-Platelet count of less than 50 x 109 cells/L: Hold avapritinib therapy. When the platelet count is 50 x 109 cells/L or more, resume treatment at a reduced dose. Consider platelet support if the platelet count does not recover.
Maximum Dosage Limits:
-Adults
300 mg/day PO.
-Geriatric
300 mg/day PO.
-Adolescents
Safety and effectiveness have not been established.
-Children
Safety and effectiveness have not been established.
Patients with Hepatic Impairment Dosing
-Mild hepatic impairment (total bilirubin level at the ULN or less and AST level more than the ULN; OR total bilirubin level of 1 to 1.5 times the ULN and any AST level): No dosage adjustment is necessary.
-Moderate hepatic impairment (total bilirubin level more than 1.5 to 3 times the ULN and any AST level): No dosage adjustment necessary.
-Severe hepatic impairment (Child-Pugh class C): Reduce the initial avapritinib dosage to 200 mg/day PO for GIST, 100 mg/day PO for AdvSM, and 25 mg PO every other day for ISM.
Patients with Renal Impairment Dosing
-Mild to moderate renal impairment (CrCl 30 to 89 mL/min): No dosage adjustment is necessary.
-Severe renal impairment (CrCl 15 to 29 mL/min) or end-stage renal disease (CrCl less than 15 mL/min): The recommended dose of avapritinib has not been established.
*non-FDA-approved indication
Adagrasib: (Major) Avoid coadministration of avapritinib with adagrasib due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor is predicted to increase the overall exposure of avapritinib by 600% at steady-state.
Amobarbital: (Major) Avoid coadministration of avapritinib with amobarbital due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate and amobarbital is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer is predicted to decrease the AUC and Cmax of avapritinib by 62% and 55%, respectively.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of avapritinib with clarithromycin due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state.
Apalutamide: (Major) Avoid coadministration of avapritinib with apalutamide due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of avapritinib by 92% and 74%, respectively.
Aprepitant, Fosaprepitant: (Major) Avoid coadministration of avapritinib with a 3-day regimen of oral aprepitant due to the risk of increased avapritinib-related adverse reactions. If concurrent use is unavoidable, reduce the starting dose of avapritinib from 300 mg PO once daily to 100 mg PO once daily in patients with gastrointestinal stromal tumor or from 200 mg PO once daily to 50 mg PO once daily in patients with advanced systemic mastocytosis. Avapritinib is a CYP3A4 substrate and the 3-day oral aprepitant regimen acts as a moderate CYP3A4 inhibitor. Coadministration of avapritinib 300 mg PO once daily with a moderate CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 210% at steady-state. Single oral doses of aprepitant and IV doses of fosaprepitant have not been shown to alter concentrations of CYP3A4 substrates.
Aspirin, ASA; Butalbital; Caffeine: (Major) Avoid coadministration of avapritinib with butalbital due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate and butalbital is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer is predicted to decrease the AUC and Cmax of avapritinib by 62% and 55%, respectively.
Atazanavir: (Major) Avoid coadministration of avapritinib with atazanavir due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and atazanavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state.
Atazanavir; Cobicistat: (Major) Avoid coadministration of avapritinib with atazanavir due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and atazanavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state. (Major) Avoid coadministration of avapritinib with cobicistat due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state.
Berotralstat: (Major) Avoid coadministration of avapritinib with berotralstat due to the risk of increased avapritinib-related adverse reactions. If concurrent use is unavoidable, reduce the starting dose of avapritinib from 300 mg PO once daily to 100 mg PO once daily in patients with gastrointestinal stromal tumor or from 200 mg PO once daily to 50 mg PO once daily in patients with advanced systemic mastocytosis. Avapritinib is a CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor. Coadministration of avapritinib 300 mg PO once daily with a moderate CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 210% at steady-state.
Bexarotene: (Major) Avoid coadministration of avapritinib with bexarotene due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate and bexarotene is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer is predicted to decrease the AUC and Cmax of avapritinib by 62% and 55%, respectively.
Bosentan: (Major) Avoid coadministration of avapritinib with bosentan due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate and bosentan is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer is predicted to decrease the AUC and Cmax of avapritinib by 62% and 55%, respectively.
Butalbital; Acetaminophen: (Major) Avoid coadministration of avapritinib with butalbital due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate and butalbital is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer is predicted to decrease the AUC and Cmax of avapritinib by 62% and 55%, respectively.
Butalbital; Acetaminophen; Caffeine: (Major) Avoid coadministration of avapritinib with butalbital due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate and butalbital is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer is predicted to decrease the AUC and Cmax of avapritinib by 62% and 55%, respectively.
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Avoid coadministration of avapritinib with butalbital due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate and butalbital is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer is predicted to decrease the AUC and Cmax of avapritinib by 62% and 55%, respectively.
Butalbital; Aspirin; Caffeine; Codeine: (Major) Avoid coadministration of avapritinib with butalbital due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate and butalbital is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer is predicted to decrease the AUC and Cmax of avapritinib by 62% and 55%, respectively.
Carbamazepine: (Major) Avoid coadministration of avapritinib with carbamazepine due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate and carbamazepine is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased the AUC and Cmax of avapritinib by 62% and 55%, respectively.
Cenobamate: (Major) Avoid coadministration of avapritinib with cenobamate due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer is predicted to decrease the AUC and Cmax of avapritinib by 62% and 55%, respectively.
Ceritinib: (Major) Avoid coadministration of avapritinib with ceritinib due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state.
Chloramphenicol: (Major) Avoid coadministration of avapritinib with chloramphenicol due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and chloramphenicol is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Ciprofloxacin: (Major) Avoid coadministration of avapritinib with ciprofloxacin due to the risk of increased avapritinib-related adverse reactions. If concurrent use is unavoidable, reduce the starting dose of avapritinib from 300 mg PO once daily to 100 mg PO once daily in patients with gastrointestinal stromal tumor or from 200 mg PO once daily to 50 mg PO once daily in patients with advanced systemic mastocytosis. Avapritinib is a CYP3A4 substrate and ciprofloxacin is a moderate CYP3A4 inhibitor. Coadministration of avapritinib 300 mg PO once daily with a moderate CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 210% at steady-state.
Clarithromycin: (Major) Avoid coadministration of avapritinib with clarithromycin due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state.
Cobicistat: (Major) Avoid coadministration of avapritinib with cobicistat due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state.
Conivaptan: (Major) Avoid coadministration of avapritinib with conivaptan due to the increased risk of avapritinib-related adverse reactions. If concurrent use is unavoidable, reduce the starting dose of avapritinib from 300 mg PO once daily to 100 mg PO once daily in patients with gastrointestinal stromal tumor or from 200 mg PO once daily to 50 mg PO once daily in patients with advanced systemic mastocytosis. Avapritinib is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor. Coadministration of avapritinib 300 mg PO once daily with a moderate CYP3A inhibitor is predicted to increase the overall exposure of avapritinib by 210%.
Crizotinib: (Major) Avoid coadministration of avapritinib with crizotinib due to the risk of increased avapritinib-related adverse reactions. If concurrent use is unavoidable, reduce the starting dose of avapritinib from 300 mg PO once daily to 100 mg PO once daily in patients with gastrointestinal stromal tumor or from 200 mg PO once daily to 50 mg PO once daily in patients with advanced systemic mastocytosis. Avapritinib is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor. Coadministration of avapritinib 300 mg PO once daily with a moderate CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 210% at steady-state.
Cyclosporine: (Major) Avoid coadministration of avapritinib with cyclosporine due to the risk of increased avapritinib-related adverse reactions. If concurrent use is unavoidable, reduce the starting dose of avapritinib from 300 mg PO once daily to 100 mg PO once daily in patients with gastrointestinal stromal tumor or from 200 mg PO once daily to 50 mg PO once daily in patients with advanced systemic mastocytosis. Avapritinib is a CYP3A4 substrate and cyclosporine is a moderate CYP3A4 inhibitor. Coadministration of avapritinib 300 mg PO once daily with a moderate CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 210% at steady-state.
Dabrafenib: (Major) Avoid coadministration of avapritinib with dabrafenib due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate and dabrafenib is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer is predicted to decrease the AUC and Cmax of avapritinib by 62% and 55%, respectively.
Danazol: (Major) Avoid coadministration of avapritinib with danazol due to the risk of increased avapritinib-related adverse reactions. If concurrent use is unavoidable, reduce the starting dose of avapritinib from 300 mg PO once daily to 100 mg PO once daily in patients with gastrointestinal stromal tumor or from 200 mg PO once daily to 50 mg PO once daily in patients with advanced systemic mastocytosis. Avapritinib is a CYP3A4 substrate and danazol is a moderate CYP3A4 inhibitor. Coadministration of avapritinib 300 mg PO once daily with a moderate CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 210% at steady-state.
Darunavir: (Major) Avoid coadministration of avapritinib with darunavir due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state.
Darunavir; Cobicistat: (Major) Avoid coadministration of avapritinib with cobicistat due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state. (Major) Avoid coadministration of avapritinib with darunavir due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid coadministration of avapritinib with cobicistat due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state. (Major) Avoid coadministration of avapritinib with darunavir due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state.
Delavirdine: (Major) Avoid coadministration of avapritinib with delavirdine due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and delavirdine is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
Diltiazem: (Major) Avoid coadministration of avapritinib with diltiazem due to the risk of increased avapritinib-related adverse reactions. If concurrent use is unavoidable, reduce the starting dose of avapritinib from 300 mg PO once daily to 100 mg PO once daily in patients with gastrointestinal stromal tumor or from 200 mg PO once daily to 50 mg PO once daily in patients with advanced systemic mastocytosis. Avapritinib is a CYP3A4 substrate and diltiazem is a moderate CYP3A4 inhibitor. Coadministration of avapritinib 300 mg PO once daily with a moderate CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 210% at steady-state.
Dronedarone: (Major) Avoid coadministration of avapritinib with dronedarone due to the risk of increased avapritinib-related adverse reactions. If concurrent use is unavoidable, reduce the starting dose of avapritinib from 300 mg PO once daily to 100 mg PO once daily in patients with gastrointestinal stromal tumor or from 200 mg PO once daily to 50 mg PO once daily in patients with advanced systemic mastocytosis. Avapritinib is a CYP3A4 substrate and dronedarone is a moderate CYP3A4 inhibitor. Coadministration of avapritinib 300 mg PO once daily with a moderate CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 210% at steady-state.
Duvelisib: (Major) Avoid coadministration of avapritinib with duvelisib due to the risk of increased avapritinib-related adverse reactions. If concurrent use is unavoidable, reduce the starting dose of avapritinib from 300 mg PO once daily to 100 mg PO once daily in patients with gastrointestinal stromal tumor or from 200 mg PO once daily to 50 mg PO once daily in patients with advanced systemic mastocytosis. Avapritinib is a CYP3A4 substrate and duvelisib is a moderate CYP3A4 inhibitor. Coadministration of avapritinib 300 mg PO once daily with a moderate CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 210% at steady-state.
Efavirenz: (Major) Avoid coadministration of avapritinib with efavirenz due to the risk of a decrease in the efficacy of avapritinib. Avapritinib is a CYP3A4 substrate and efavirenz is a strong CYP3A4 inducer. Coadministration with efavirenz is predicted to decrease the AUC and Cmax of avapritinib by 62% and 55%, respectively.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of avapritinib with efavirenz due to the risk of a decrease in the efficacy of avapritinib. Avapritinib is a CYP3A4 substrate and efavirenz is a strong CYP3A4 inducer. Coadministration with efavirenz is predicted to decrease the AUC and Cmax of avapritinib by 62% and 55%, respectively.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of avapritinib with efavirenz due to the risk of a decrease in the efficacy of avapritinib. Avapritinib is a CYP3A4 substrate and efavirenz is a strong CYP3A4 inducer. Coadministration with efavirenz is predicted to decrease the AUC and Cmax of avapritinib by 62% and 55%, respectively.
Elagolix: (Major) Avoid coadministration of avapritinib with elagolix due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate and elagolix is a weak-to-moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer is predicted to decrease the AUC and Cmax of avapritinib by 62% and 55%, respectively.
Elagolix; Estradiol; Norethindrone acetate: (Major) Avoid coadministration of avapritinib with elagolix due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate and elagolix is a weak-to-moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer is predicted to decrease the AUC and Cmax of avapritinib by 62% and 55%, respectively.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid coadministration of avapritinib with cobicistat due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of avapritinib with cobicistat due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state.
Encorafenib: (Major) Avoid coadministration of avapritinib with encorafenib due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the overall exposure and peak of avapritinib by 92% and 74%, respectively.
Enzalutamide: (Major) Avoid coadministration of avapritinib with enzalutamide due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of avapritinib by 92% and 74%, respectively.
Erythromycin: (Major) Avoid coadministration of avapritinib with erythromycin due to the risk of increased avapritinib-related adverse reactions. If concurrent use is unavoidable, reduce the starting dose of avapritinib from 300 mg PO once daily to 100 mg PO once daily in patients with gastrointestinal stromal tumor or from 200 mg PO once daily to 50 mg PO once daily in patients with advanced systemic mastocytosis. Avapritinib is a CYP3A4 substrate and erythromycin is a moderate CYP3A4 inhibitor. Coadministration of avapritinib 300 mg PO once daily with a moderate CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 210% at steady-state.
Eslicarbazepine: (Major) Avoid coadministration of avapritinib with eslicarbazepine due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate and eslicarbazepine is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer is predicted to decrease the AUC and Cmax of avapritinib by 62% and 55%, respectively.
Etravirine: (Major) Avoid coadministration of avapritinib with etravirine due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate and etravirine is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer is predicted to decrease the AUC and Cmax of avapritinib by 62% and 55%, respectively.
Fedratinib: (Major) Avoid coadministration of avapritinib with fedratinib due to the risk of increased avapritinib-related adverse reactions. If concurrent use is unavoidable, reduce the starting dose of avapritinib from 300 mg PO once daily to 100 mg PO once daily in patients with gastrointestinal stromal tumor or from 200 mg PO once daily to 50 mg PO once daily in patients with advanced systemic mastocytosis. Avapritinib is a CYP3A4 substrate and fedratinib is a moderate CYP3A4 inhibitor. Coadministration of avapritinib 300 mg PO once daily with a moderate CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 210% at steady-state.
Fluconazole: (Major) Avoid coadministration of avapritinib with fluconazole due to the risk of increased avapritinib-related adverse reactions. If concurrent use is unavoidable, reduce the starting dose of avapritinib from 300 mg PO once daily to 100 mg PO once daily in patients with gastrointestinal stromal tumor or from 200 mg PO once daily to 50 mg PO once daily in patients with advanced systemic mastocytosis. Avapritinib is a CYP3A4 substrate and fluconazole is a moderate CYP3A4 inhibitor. Coadministration of avapritinib 300 mg PO once daily with fluconazole is predicted to increase the AUC of avapritinib by 210% at steady-state.
Fluvoxamine: (Major) Avoid coadministration of avapritinib with fluvoxamine due to the risk of increased avapritinib-related adverse reactions. If concurrent use is unavoidable, reduce the starting dose of avapritinib from 300 mg PO once daily to 100 mg PO once daily in patients with gastrointestinal stromal tumor or from 200 mg PO once daily to 50 mg PO once daily in patients with advanced systemic mastocytosis. Avapritinib is a CYP3A4 substrate and fluvoxamine is a moderate CYP3A4 inhibitor. Coadministration of avapritinib 300 mg PO once daily with a moderate CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 210% at steady-state.
Fosamprenavir: (Major) Avoid coadministration of avapritinib with fosamprenavir due to the risk of increased avapritinib-related adverse reactions. If concurrent use is unavoidable, reduce the starting dose of avapritinib from 300 mg PO once daily to 100 mg PO once daily in patients with gastrointestinal stromal tumor or from 200 mg PO once daily to 50 mg PO once daily in patients with advanced systemic mastocytosis. Avapritinib is a CYP3A substrate and fosamprenavir is a moderate CYP3A inhibitor. Coadministration of avapritinib 300 mg PO once daily with another moderate CYP3A inhibitor is predicted to increase the overall exposure of avapritinib by 210% at steady-state.
Fosphenytoin: (Major) Avoid coadministration of avapritinib with fosphenytoin due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate and fosphenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of avapritinib by 92% and 74%, respectively.
Grapefruit juice: (Major) Advise patients to avoid grapefruit or grapefruit juice during avapritinib treatment due to the increased risk of avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and grapefruit juice is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state.
Idelalisib: (Major) Avoid coadministration of avapritinib with idelalisib due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and idelalisib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state.
Imatinib: (Major) Avoid coadministration of avapritinib with imatinib due to the risk of increased avapritinib-related adverse reactions. If concurrent use is unavoidable, reduce the starting dose of avapritinib from 300 mg PO once daily to 100 mg PO once daily in patients with gastrointestinal stromal tumor or from 200 mg PO once daily to 50 mg PO once daily in patients with advanced systemic mastocytosis. Avapritinib is a CYP3A4 substrate and imatinib is a moderate CYP3A4 inhibitor. Coadministration of avapritinib 300 mg PO once daily with a moderate CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 210% at steady-state.
Indinavir: (Major) Avoid coadministration of avapritinib with indinavir due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and indinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state.
Isavuconazonium: (Major) Avoid coadministration of avapritinib with isavuconazonium due to the risk of increased avapritinib-related adverse reactions. If concurrent use is unavoidable, reduce the starting dose of avapritinib from 300 mg PO once daily to 100 mg PO once daily in patients with gastrointestinal stromal tumor or from 200 mg PO once daily to 50 mg PO once daily in patients with advanced systemic mastocytosis. Avapritinib is a CYP3A4 substrate and isavuconazonium is a moderate CYP3A4 inhibitor. Coadministration of avapritinib 300 mg PO once daily with a moderate CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 210% at steady-state.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of avapritinib with rifampin due to the risk of a decrease in the efficacy of avapritinib. Avapritinib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased the AUC and Cmax of avapritinib by 92% and 74%, respectively.
Isoniazid, INH; Rifampin: (Major) Avoid coadministration of avapritinib with rifampin due to the risk of a decrease in the efficacy of avapritinib. Avapritinib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased the AUC and Cmax of avapritinib by 92% and 74%, respectively.
Itraconazole: (Major) Avoid coadministration of avapritinib with itraconazole due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and itraconazole is a strong CYP3A4 inhibitor. Coadministration with itraconazole is predicted to increase the AUC of avapritinib by 600% at steady-state.
Ketoconazole: (Major) Avoid coadministration of avapritinib with ketoconazole due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid coadministration of avapritinib with clarithromycin due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state.
Lefamulin: (Major) Avoid coadministration of avapritinib with oral lefamulin due to the risk of increased avapritinib-related adverse reactions. If concurrent use is unavoidable, reduce the starting dose of avapritinib from 300 mg PO once daily to 100 mg PO once daily in patients with gastrointestinal stromal tumor or from 200 mg PO once daily to 50 mg PO once daily in patients with advanced systemic mastocytosis. Avapritinib is a CYP3A4 substrate and oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. Coadministration of avapritinib 300 mg PO once daily with a moderate CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 210% at steady-state.
Lenacapavir: (Major) Avoid coadministration of avapritinib with lenacapavir due to the risk of increased avapritinib-related adverse reactions. If concurrent use is unavoidable, reduce the starting dose of avapritinib from 300 mg PO once daily to 100 mg PO once daily in patients with gastrointestinal stromal tumor or from 200 mg PO once daily to 50 mg PO once daily in patients with advanced systemic mastocytosis. Avapritinib is a CYP3A substrate and lenacapavir is a moderate CYP3A inhibitor. Coadministration of avapritinib 300 mg PO once daily with another moderate CYP3A inhibitor is predicted to increase the overall exposure of avapritinib by 210% at steady-state.
Letermovir: (Major) Avoid coadministration of avapritinib with letermovir due to the risk of increased avapritinib-related adverse reactions. If concurrent use is unavoidable, reduce the starting dose of avapritinib from 300 mg PO once daily to 100 mg PO once daily in patients with gastrointestinal stromal tumor or from 200 mg PO once daily to 50 mg PO once daily in patients with advanced systemic mastocytosis. Avoid concomitant use in patients also receiving cyclosporine because the magnitude of the interaction may be increased. Avapritinib is a CYP3A4 substrate and letermovir is a moderate CYP3A4 inhibitor; however, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 210% at steady-state. Coadministration of avapritinib 300 mg PO once daily with a strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state.
Levoketoconazole: (Major) Avoid coadministration of avapritinib with ketoconazole due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state.
Lonafarnib: (Major) Avoid coadministration of avapritinib with lonafarnib due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state.
Lopinavir; Ritonavir: (Major) Avoid coadministration of avapritinib with ritonavir due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state.
Lorlatinib: (Major) Avoid coadministration of avapritinib with lorlatinib due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer is predicted to decrease the AUC and Cmax of avapritinib by 62% and 55%, respectively.
Lumacaftor; Ivacaftor: (Major) Avoid coadministration of avapritinib with lumacaftor; ivacaftor due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of avapritinib by 92% and 74%, respectively.
Lumacaftor; Ivacaftor: (Major) Avoid coadministration of avapritinib with lumacaftor; ivacaftor due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of avapritinib by 92% and 74%, respectively.
Mavacamten: (Major) Avoid coadministration of avapritinib with mavacamten due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A substrate and mavacamten is a moderate CYP3A inducer. Coadministration with another moderate CYP3A inducer is predicted to decrease the overall exposure and peak of avapritinib by 62% and 55%, respectively.
Methohexital: (Major) Avoid coadministration of avapritinib with methohexital due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate and methohexital is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer is predicted to decrease the AUC and Cmax of avapritinib by 62% and 55%, respectively.
Mifepristone: (Major) Avoid coadministration of avapritinib with mifepristone due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and mifepristone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state. The clinical significance of this interaction with the short-term use of mifepristone for termination of pregnancy is unknown.
Mitotane: (Major) Avoid coadministration of avapritinib with mitotane due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of avapritinib by 92% and 74%, respectively.
Modafinil: (Major) Avoid coadministration of avapritinib with modafinil due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate and modafinil is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer is predicted to decrease the AUC and Cmax of avapritinib by 62% and 55%, respectively.
Nafcillin: (Major) Avoid coadministration of avapritinib with nafcillin due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate and nafcillin is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer is predicted to decrease the AUC and Cmax of avapritinib by 62% and 55%, respectively.
Nefazodone: (Major) Avoid coadministration of avapritinib with nefazodone due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state.
Nelfinavir: (Major) Avoid coadministration of avapritinib with nelfinavir due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and nelfinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state.
Netupitant, Fosnetupitant; Palonosetron: (Major) Avoid coadministration of avapritinib with netupitant due to the risk of increased avapritinib-related adverse reactions. If concurrent use is unavoidable, reduce the starting dose of avapritinib from 300 mg PO once daily to 100 mg PO once daily in patients with gastrointestinal stromal tumor or from 200 mg PO once daily to 50 mg PO once daily in patients with advanced systemic mastocytosis. Avapritinib is a CYP3A4 substrate and netupitant is a moderate CYP3A4 inhibitor. Coadministration of avapritinib 300 mg PO once daily with a moderate CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 210% at steady-state.
Nilotinib: (Major) Avoid coadministration of avapritinib with nilotinib due to the risk of increased avapritinib-related adverse reactions. If concurrent use is unavoidable, reduce the starting dose of avapritinib from 300 mg PO once daily to 100 mg PO once daily in patients with gastrointestinal stromal tumor or from 200 mg PO once daily to 50 mg PO once daily in patients with advanced systemic mastocytosis. Avapritinib is a CYP3A4 substrate and nilotinib is a moderate CYP3A4 inhibitor. Coadministration of avapritinib 300 mg PO once daily with a moderate CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 210% at steady-state.
Nirmatrelvir; Ritonavir: (Major) Avoid coadministration of avapritinib with ritonavir due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state.
Nirogacestat: (Major) Avoid coadministration of avapritinib with nirogacestat due to the risk of increased avapritinib-related adverse reactions. If concurrent use is unavoidable, reduce the starting dose of avapritinib from 300 mg PO once daily to 100 mg PO once daily in patients with gastrointestinal stromal tumor or from 200 mg PO once daily to 50 mg PO once daily in patients with advanced systemic mastocytosis. Avapritinib is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor. Coadministration of avapritinib 300 mg PO once daily with another moderate CYP3A inhibitor is predicted to increase the overall exposure of avapritinib by 210% at steady-state.
Omeprazole; Amoxicillin; Rifabutin: (Major) Avoid coadministration of avapritinib with rifabutin due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer is predicted to decrease the AUC and Cmax of avapritinib by 62% and 55%, respectively.
Pentobarbital: (Major) Avoid coadministration of avapritinib with pentobarbital due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate and pentobarbital is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer is predicted to decrease the AUC and Cmax of avapritinib by 62% and 55%, respectively.
Pexidartinib: (Major) Avoid coadministration of avapritinib with pexidartinib due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate and pexidartinib is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer is predicted to decrease the AUC and Cmax of avapritinib by 62% and 55%, respectively.
Phenobarbital: (Major) Avoid coadministration of avapritinib with phenobarbital due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of avapritinib by 92% and 74%, respectively.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid coadministration of avapritinib with phenobarbital due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of avapritinib by 92% and 74%, respectively.
Phenytoin: (Major) Avoid coadministration of avapritinib with phenytoin due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of avapritinib by 92% and 74%, respectively.
Posaconazole: (Major) Avoid coadministration of avapritinib with posaconazole due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and posaconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state.
Primidone: (Major) Avoid coadministration of avapritinib with primidone due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of avapritinib by 92% and 74%, respectively.
Repotrectinib: (Major) Avoid coadministration of avapritinib with repotrectinib due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A substrate and repotrectinib is a moderate CYP3A inducer. Coadministration with another moderate CYP3A inducer is predicted to decrease the overall exposure and peak of avapritinib by 62% and 55%, respectively.
Ribociclib: (Major) Avoid coadministration of avapritinib with ribociclib due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state.
Ribociclib; Letrozole: (Major) Avoid coadministration of avapritinib with ribociclib due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state.
Rifabutin: (Major) Avoid coadministration of avapritinib with rifabutin due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer is predicted to decrease the AUC and Cmax of avapritinib by 62% and 55%, respectively.
Rifampin: (Major) Avoid coadministration of avapritinib with rifampin due to the risk of a decrease in the efficacy of avapritinib. Avapritinib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased the AUC and Cmax of avapritinib by 92% and 74%, respectively.
Rifapentine: (Major) Avoid coadministration of avapritinib with rifapentine due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of avapritinib by 92% and 74%, respectively.
Ritlecitinib: (Major) Avoid coadministration of avapritinib with ritlecitinib due to the risk of increased avapritinib-related adverse reactions. If concurrent use is unavoidable, reduce the starting dose of avapritinib from 300 mg PO once daily to 100 mg PO once daily in patients with gastrointestinal stromal tumor or from 200 mg PO once daily to 50 mg PO once daily in patients with advanced systemic mastocytosis. Avapritinib is a CYP3A substrate and ritlecitinib is a moderate CYP3A inhibitor. Coadministration of avapritinib 300 mg PO once daily with another moderate CYP3A inhibitor is predicted to increase the overall exposure of avapritinib by 210% at steady-state.
Ritonavir: (Major) Avoid coadministration of avapritinib with ritonavir due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state.
Saquinavir: (Major) Avoid coadministration of avapritinib with saquinavir due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and saquinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Secobarbital: (Major) Avoid coadministration of avapritinib with secobarbital due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate and secobarbital is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer is predicted to decrease the AUC and Cmax of avapritinib by 62% and 55%, respectively.
Sotorasib: (Major) Avoid coadministration of avapritinib with sotorasib due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer is predicted to decrease the AUC and Cmax of avapritinib by 62% and 55%, respectively.
St. John's Wort, Hypericum perforatum: (Major) Avoid coadministration of avapritinib with St. John's Wort due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of avapritinib by 92% and 74%, respectively.
Tipranavir: (Major) Avoid coadministration of avapritinib with tipranavir due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and tipranavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state.
Trandolapril; Verapamil: (Major) Avoid coadministration of avapritinib with verapamil due to the risk of increased avapritinib-related adverse reactions. If concurrent use is unavoidable, reduce the starting dose of avapritinib from 300 mg PO once daily to 100 mg PO once daily in patients with gastrointestinal stromal tumor or from 200 mg PO once daily to 50 mg PO once daily in patients with advanced systemic mastocytosis. Avapritinib is a CYP3A4 substrate and verapamil is a moderate CYP3A4 inhibitor. Coadministration of avapritinib 300 mg PO once daily with a moderate CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 210% at steady-state.
Tucatinib: (Major) Avoid coadministration of avapritinib with tucatinib due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state.
Verapamil: (Major) Avoid coadministration of avapritinib with verapamil due to the risk of increased avapritinib-related adverse reactions. If concurrent use is unavoidable, reduce the starting dose of avapritinib from 300 mg PO once daily to 100 mg PO once daily in patients with gastrointestinal stromal tumor or from 200 mg PO once daily to 50 mg PO once daily in patients with advanced systemic mastocytosis. Avapritinib is a CYP3A4 substrate and verapamil is a moderate CYP3A4 inhibitor. Coadministration of avapritinib 300 mg PO once daily with a moderate CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 210% at steady-state.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid coadministration of avapritinib with clarithromycin due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state.
Voriconazole: (Major) Avoid coadministration of avapritinib with voriconazole due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state.
Voxelotor: (Major) Avoid coadministration of avapritinib with voxelotor due to the risk of increased avapritinib-related adverse reactions. If concurrent use is unavoidable, reduce the starting dose of avapritinib from 300 mg PO once daily to 100 mg PO once daily in patients with gastrointestinal stromal tumor or from 200 mg PO once daily to 50 mg PO once daily in patients with advanced systemic mastocytosis. Avapritinib is a CYP3A substrate and voxelotor is a moderate CYP3A inhibitor. Coadministration of avapritinib 300 mg PO once daily with another moderate CYP3A inhibitor is predicted to increase the overall exposure of avapritinib by 210% at steady-state.
Avapritinib is a tyrosine kinase inhibitor that targets KIT D816V and platelet-derived growth factor receptor alpha (PDGFRA) mutations (e.g., PDGFRA D842V mutants) and multiple KIT exon 11, 11/17, and 17 mutants at half-maximal inhibitory concentrations (IC50) of less than 25 nanomolar. 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, PDGFR beta, and CSFR1. In cellular assays, avapritinib inhibited the autophosphorylation of KIT D816V and PDGFRA D842V with IC50 values of 4 and 30 nanomolar, respectively. Avapritinib inhibits KIT D816V at concentrations about 48-times lower than wild-type KIT. Additionally, proliferation of KIT-mutant cell lines including murine mastocytoma cells and human mast cell leukemia cells was inhibited by avapritinib; inhibitory activity was also observed in a xenograft model of murine mastocytoma with KIT exon 17 mutation. Avapritinib exhibited antitumor activity in mice implanted with an imatinib-resistant patient-derived xenograft model of human GIST with activating KIT exon 11/17 mutations.
Avapritinib is administered orally. It is 98.8% protein-bound in vitro, independent of concentration; the blood-to-plasma ratio is 0.95. At recommended doses, the mean apparent volumes of distribution are 1,310 L (coefficient of variation (CV), 51.5%) in patients with gastrointestinal stromal tumor (GIST), 1,900 L (CV, 43.2%) in patients with advanced systemic mastocytosis (AdvSM), and 1,400 L (CV, 59.1%) in patients with indolent systemic mastocytosis (ISM); the steady-state mean apparent oral clearances of avapritinib are 21.8 (CV, 54.9%), 40.3 (CV, 86%), and 21.6 (CV, 58.1%) L/hour, respectively. Following a single dose of avapritinib, the mean plasma elimination half-lives of avapritinib were 32 to 57 hours in patients with GIST, 20 to 39 hours in patients with AdvSM, and 38 to 45 hours in patients with ISM. Avapritinib is primarily metabolized in the liver by CYP3A4/5. After a single radiolabeled oral avapritinib dose of approximately 310 mg to healthy subjects, unchanged avapritinib (49%) and its metabolites M690 (hydroxy glucuronide catalyzed mainly by UGT1A3; 35%) and M499 (oxidative deamination; 14%) were the major circulating compounds; 70% of radioactivity was recovered in feces (11% unchanged) and 18% in urine (0.23% unchanged). After administration of avapritinib 300 mg once daily, the steady-state AUC of M499 is approximately 80% of the AUC of avapritinib; M499 is not likely to contribute to efficacy at the recommended dose of avapritinib.
Affected cytochrome P450 isoenzymes or transporters: CYP3A4/5
Avapritinib is a substrate of CYP3A4/5; it is also a CYP2C9 substrate to a lesser extent in vitro. In vitro, avapritinib is also a time-dependent CYP3A inhibitor, a CYP2C9 inhibitor, and a CYP3A inducer at clinically relevant concentrations. It additionally inhibits P-gp, intestinal BCRP, MATE1, MATE2K, and BSEP in vitro. Metabolite M499 inhibits CYP3A, CYP2C8, and CYP2C9 at clinically relevant concentrations; the effect of M499 on transporter systems is unknown.
-Route-Specific Pharmacokinetics
Oral Route
The steady-state geometric mean Cmax and AUC(0-24h) values were 813 (coefficient of variation (CV), 52%) nanogram (ng)/mL and 15,400 (CV, 48%) ng x hour/mL, respectively, following avapritinib 300 mg PO once daily in patients with gastrointestinal stromal tumor (GIST; n = 110). The steady-state geometric mean Cmax and AUC(0-24h) values were 377 (CV, 62%) ng/mL (n = 18) and 6,600 (CV, 54%) ng x hour/mL (n = 16), respectively, following avapritinib 200 mg PO once daily in patients with advanced systemic mastocytosis (AdvSM). The steady-state geometric mean Cmax and AUC(0-24h) values were 70.2 (CV, 47.8%) ng/mL and 1,330 (CV, 49.5%) ng x hour/mL, respectively, following avapritinib 25 mg PO once daily in patients with indolent systemic mastocytosis (ISM; n = 9). The Cmax and AUC values increased proportionally over an avapritinib dose range of 25 mg to 400 mg once daily. The mean time-to-peak concentration (Tmax) ranged from 2 to 4 hours following single doses of avapritinib. Steady-state concentrations of avapritinib were reached by day 15 after daily administration; the mean accumulation ratios at steady state were 3.82 (n = 34), 6.41 (n = 9), and 4.06 (n = 9) in patients with GIST (300 mg/day), AdvSM (200 mg/day), and ISM (35 mg/day), respectively. Based on data from 4 clinicals trials, higher avapritinib exposure was associated with an increased risk of grade 3 or higher treatment-related adverse effects, any grade pooled cognitive adverse effects, grade 2 or higher pooled cognitive adverse effects, and grade 2 or higher pooled edema adverse effects over the dose range of 30 mg to 400 mg once daily in patients with advanced malignancies or systemic mastocytosis. Higher avapritinib exposure was associated with a faster time to response in patients with AdvSM.
Effects of food: When administered with a high-calorie, high-fat meal (approximately 909 calories with 58 g carbohydrate, 56 g fat, and 43 g protein), the avapritinib Cmax and AUC values were increased by 59% and 29%, respectively, compared to those in a fasted state. Coadministration with gastric acid reducing agents does not cause a clinically significant difference in the pharmacokinetics of avapritinib in patients with GIST or AdvSM.
-Special Populations
Hepatic Impairment
Mild (total bilirubin level at the ULN or less and AST level more than ULN; OR total bilirubin level 1 to 1.5 times the ULN and any AST level) or moderate (total bilirubin level more than 1.5 to 3 times the ULN and any AST level) hepatic impairment do not have a clinically significant effect on the pharmacokinetics of avapritinib. Following a single oral avapritinib 100-mg dose, the mean unbound AUC(0-inf) value was 61% higher in subjects with severe hepatic impairment (Child-Pugh Class C) compared with healthy subjects with normal hepatic function.
Renal Impairment
Mild to moderate renal impairment (CrCl 30 to 89 mL/min) does not have a clinically significant effect on the pharmacokinetics of avapritinib. The effect of severe renal impairment (CrCl 15 to 29 mL/min) or end-stage renal disease (CrCl less than 15 mL/min) on the pharmacokinetics of avapritinib is unknown.
Geriatric
Age (18 to 90 years) does not have a clinically significant effect on the pharmacokinetics of avapritinib.
Gender Differences
Gender does not have a clinically significant effect on the pharmacokinetics of avapritinib.
Ethnic Differences
Ethnicity (White, Black, Asian) does not have a clinically significant effect on the pharmacokinetics of avapritinib.
Obesity
Body weight (39.5 kg to 156.3 kg) does not have a clinically significant effect on the pharmacokinetics of avapritinib.