Note: Avapritinib is associated with a moderate or high emetic potential; antiemetics may be recommended to prevent nausea and vomiting (ASCO [Hesketh 2020]). For the treatment of advanced systemic mastocytosis, use is not recommended if platelet count is <50,000/mm3.
Gastrointestinal stromal tumor, unresectable or metastatic, with a PDGFRA exon 18 mutation: Oral: 300 mg once daily until disease progression or unacceptable toxicity (Heinrich 2020).
Systemic mastocytosis, advanced: Oral: 200 mg once daily until disease progression or unacceptable toxicity.
Missed/vomited doses: Do not make up for a missed dose within 8 hours of the next scheduled dose. If vomiting occurs, do not repeat dose; resume dosing with the next scheduled daily dose.
Dosage adjustment for concomitant therapy: Significant drug Interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug Interactions database for more information.
Note: Kidney function estimated by Cockcroft-Gault equation.
CrCl 30 to 89 mL/minute: No dosage adjustment necessary.
CrCl ≤29 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling.
End-stage renal disease: There are no dosage adjustments provided in the manufacturer's labeling.
Mild (total bilirubin ≤ ULN and AST > ULN or total bilirubin 1 to 1.5 times ULN and any AST) or moderate (total bilirubin >1.5 to 3 times ULN and any AST) impairment: No dosage adjustment necessary.
Severe impairment (total bilirubin >3 times ULN and any AST): There are no dosage adjustments provided in the manufacturer's labeling.
Refer to adult dosing.
GIST |
Systemic mastocytosis | |
---|---|---|
Initial (usual) dose |
300 mg once daily |
200 mg once daily |
First dose reduction |
200 mg once daily |
100 mg once daily |
Second dose reduction |
100 mg once daily |
50 mg once daily |
Third dose reduction |
N/A |
25 mg once daily |
If further dose reductions are necessary |
Permanently discontinue avapritinib in patients with GIST unable to tolerate 100 mg once daily. |
Permanently discontinue avapritinib in patients with systemic mastocytosis unable to tolerate 25 mg once daily. |
Adverse reaction |
Severity |
Dose modification |
---|---|---|
GIST or advanced systemic mastocytosis | ||
Cognitive effects |
Grade 1 |
Continue avapritinib at the same or a reduced dose or withhold dose until improvement to baseline or resolution; resume at the same or at a reduced dose. |
Grade 2 or 3 |
Withhold avapritinib until improvement to baseline, grade 1, or resolution; resume at the same or at a reduced dose. | |
Grade 4 |
Permanently discontinue avapritinib. | |
Intracranial hemorrhage |
Any grade |
Permanently discontinue avapritinib. |
Other toxicity |
Grade 3 or 4 |
Withhold avapritinib until improvement to ≤ grade 2; resume at the same or at a reduced dose per clinical assessment. |
Advanced systemic mastocytosis | ||
Thrombocytopenia |
Platelets <50,000/mm3 |
Interrupt avapritinib until platelets are ≥50,000/mm3, then resume at a reduced dose. Consider platelet support if platelets do not recover to >50,000/mm3. |
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Ayvakit: 25 mg, 50 mg, 100 mg, 200 mg, 300 mg
No
Avapritinib is available through a select network of specialty pharmacies. For more information, refer to https://ayvakit.com/hcp/.
Oral: Administer on an empty stomach, at least 1 hour before or 2 hours after a meal. Avapritinib is associated with a moderate or high emetic potential; antiemetics may be recommended to prevent nausea and vomiting (ASCO [Hesketh 2020]).
This medication is not on the NIOSH (2016) list; however, it may meet the criteria for a hazardous drug. Avapritinib may cause reproductive toxicity, teratogenicity, and has a structural or toxicity profile similar to existing hazardous agents.
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.
Gastrointestinal stromal tumor, unresectable or metastatic: Treatment of unresectable or metastatic gastrointestinal stromal tumor harboring a PDGFRA exon 18 mutation, including PDGFRA D842V mutations in adults.
Systemic mastocytosis, advanced: Treatment of advanced systemic mastocytosis (AdvSM) in adults, including aggressive systemic mastocytosis, systemic mastocytosis with an associated hematological neoplasm, and mast cell leukemia.
Limitations of use: Avapritinib is not recommended for the treatment of patients with AdvSM with platelet counts of <50,000/mm3.
Avapritinib may be confused with acalabrutinib, afatinib, alectinib, alpelisib, amivantamab, axitinib, enasidenib, ibrutinib, imatinib, ripretinib.
This medication is in a class the Institute for Safe Medication Practices includes among its lists of drug classes which have a heightened risk of causing significant patient harm when used in error.
Cognitive effects are common with use including cognitive dysfunction (eg, memory impairment, confusion, disturbance in attention, mental status changes, amnesia [including retrograde amnesia], encephalopathy, dementia, abnormality in thinking). Other CNS effects include dizziness, fatigue, and speech disturbance. Cognitive and other CNS effects are typically mild to moderate; however, severe effects (≥ grade 3) may occur, particularly cognitive dysfunction and fatigue. Memory impairment is the most frequent type of cognitive dysfunction reported. Most cognitive and other CNS effects appear to be reversible following dose reductions or short interruptions (Ref); however, some adverse reactions may require discontinuation.
Onset: Varied; median time to onset of the first cognitive effect was ~11 weeks (range: 1 day to 4 years).
Various types of edema (eg, facial edema, peripheral edema, generalized edema) are commonly reported. Periorbital edema, in particular, is associated with use and may be severe (Ref).
Abdominal pain, constipation, decreased appetite, diarrhea, nausea, and vomiting are common; GI events are usually grade 1 and 2, although may sometimes be severe. Avapritinib is associated with a moderate emetic potential.
Intracranial hemorrhage, including subdural hematoma and cerebral hemorrhage, has been infrequently observed with use (Ref).
Onset: Delayed; onset of intracranial hemorrhage ranged from ~2 to 19 months after initiation.
Decreased platelet count, decreased neutrophils, and leukopenia are common and may be severe. Anemia is also frequently observed and may be severe (Ref). Decreased platelet count is generally reversible following dose reduction or therapy interruption.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Incidence of adverse reactions include unapproved dosing regimens. Reported adverse reactions are for adults.
>10%:
Cardiovascular: Edema (72% to 79%), peripheral edema (Gilreath 2019)
Dermatologic: Alopecia (9% to 13%), hair discoloration (6% to 21%), skin rash (8% to 23%)
Endocrine & metabolic: Decreased serum albumin (15% to 31%), decreased serum calcium (50%), decreased serum magnesium (14% to 29%), decreased serum phosphate (9% to 49%), decreased serum potassium (26% to 34%), decreased serum sodium (18% to 28%), increased serum potassium (11%), weight loss (13%)
Gastrointestinal: Abdominal pain (14% to 31%; severe abdominal pain: 3%), ageusia (≤15%), constipation (11% to 23%), decreased appetite (8% to 38%), diarrhea (28% to 37%; grades ≥3: 1% to 5%), dysgeusia (≤15%), dyspepsia (16%), nausea (24% to 64%; grades ≥3: 1% to 3%), vomiting (18% to 38%; grades ≥3: 2% to 3%)
Hematologic & oncologic: Decreased neutrophils (43% to 54%; grades ≥3: 6% to 25%), decreased platelet count (27% to 64%; grades ≥3: <21%), increased INR (24%; grades ≥3: <1%), leukopenia (62%; grades ≥3: 5%), lymphocytopenia (34%: grades ≥3: 11%), prolonged partial thromboplastin time (13% to 14%; grades ≥3: 1%)
Hepatic: Increased serum alanine aminotransferase (18% to 19%), increased serum alkaline phosphatase (14% to 24%), increased serum aspartate aminotransferase (38% to 51%), increased serum bilirubin (41% to 69%)
Nervous system: Cognitive dysfunction (including disturbance in attention, mental status changes, dementia, abnormality in thinking: 14% to 48%; grades 3/4: 1% to 5%), dizziness (13% to 22%), fatigue (≤61%; grades ≥3: ≤9%), headache (15% to 17%), memory impairment (26% to 29%) (Farag 2020, Martin-Broto 2020), mood disorder (including agitation, anxiety, depression, dysphoria, irritability, nervousness, personality changes, suicidal ideation; 13%), sleep disorder (16%)
Neuromuscular & skeletal: Asthenia (≤61%)
Ophthalmic: Increased lacrimation (9% to 33%), periorbital edema (Farag 2020, Gilreath 2019)
Renal: Increased serum creatinine (20% to 29%)
Respiratory: Dyspnea (9% to 17%), epistaxis (11%), pleural effusion (3% to 12%)
Miscellaneous: Fever (14%)
1% to 10%:
Cardiovascular: Cardiac failure (1% to 3%), flushing (4%), hypertension (4% to 8%), hypotension (4%), subdural hematoma (4%)
Dermatologic: Palmar-plantar erythrodysesthesia (1%), pruritus (8%)
Endocrine & metabolic: Hot flash (3%), hyperthyroidism (≤3%), hypothyroidism (≤3%), thyroid disease (3%)
Gastrointestinal: Cholelithiasis (1%), gastrointestinal hemorrhage (1% to 2%), intestinal perforation (1% to 2%)
Genitourinary: Urinary tract infection (6%)
Hematologic & oncologic: Anemia (5% to 9%), lymphocytosis (10%), tumor hemorrhage (1%)
Hepatic: Ascites (5%)
Infection: Herpes zoster infection (3%), sepsis (3%)
Nervous system: Amnesia (including retrograde amnesia; 3%), confusion (6%), drowsiness (2%), encephalopathy (2%), insomnia (6%), intracranial hemorrhage (1% to 3%), speech disturbance (2%)
Neuromuscular & skeletal: Arthralgia (10%), limb pain (6%)
Renal: Acute kidney injury (2%)
Respiratory: Cough (3%), pneumonia (1% to 3%), upper respiratory tract infection (6%)
Frequency not defined:
Cardiovascular: Facial edema
Genitourinary: Testicular swelling
Nervous system: Cerebral hemorrhage
Respiratory: Pharyngeal edema
There are no contraindications listed in the manufacturer's labeling.
Dosage form specific issues :
• Propylene glycol: Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP 1997; Zar 2007). See manufacturer's labeling.
Other warnings/precautions:
• PDGFRA exon 18 mutation: Select patients for the treatment of unresectable or metastatic gastrointestinal stromal tumor based on the presence of a PDGFRA exon 18 mutation. In a clinical study, PDGFRA exon 18 mutations were identified by local or central assessment using a polymerase chain reaction– or next-generation sequencing–based assay.
Substrate of CYP2C9 (minor), CYP3A4 (major), UGT1A3; Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy
Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modification
Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy
Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Bromopride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider therapy modification
Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: Monitor therapy
Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider therapy modification
Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Avapritinib. Risk X: Avoid combination
CYP3A4 Inducers (Strong): May decrease the serum concentration of Avapritinib. Risk X: Avoid combination
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Avapritinib. Management: Avoid use of moderate CYP3A4 inhibitors with avapritinib. If this combination cannot be avoided, reduce the avapritinib dose to 100 mg daily for the treatment of GIST or to 50 mg daily for the treatment of advanced systemic mastocytosis. Risk D: Consider therapy modification
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Avapritinib. Risk X: Avoid combination
Daridorexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification
Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Risk C: Monitor therapy
Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification
Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy
Esketamine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modification
HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy
Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider therapy modification
Lisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider therapy modification
Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy
Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification
Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination
Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Oxybate Salt Products: CNS Depressants may enhance the CNS depressant effect of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider therapy modification
OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification
Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination
Perampanel: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Risk C: Monitor therapy
Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Risk C: Monitor therapy
Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modification
ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy
Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy
Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy
Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification
Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination
Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider therapy modification
The Cmax and AUC0-∞ were increased by 59% and 29%, respectively, when administered with a high-calorie, high-fat meal (compared to fasting). Management: Administer avapritinib at least 1 hour before or 2 hours after a meal.
Evaluate pregnancy status prior to use in females of reproductive potential. Females of reproductive potential and males with female partners of reproductive potential should use effective contraception during therapy and for 6 weeks after the last dose of avapritinib.
Based on the mechanism of action and data from animal reproduction studies, in utero exposure to avapritinib may cause fetal harm.
It is not known if avapritinib is present in breast milk.
Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer during treatment and for 2 weeks after the last avapritinib dose.
Assess PDGFRA exon 18 mutation status for use in patients with gastrointestinal stromal tumor (GIST). For advanced systemic mastocytosis, obtain a platelet count prior to therapy initiation, then every 2 weeks for the first 8 weeks (regardless of baseline platelet count). After 8 weeks of therapy, monitor platelet count every 2 weeks (or more frequently if clinically necessary) if platelets are <75,000/mm3, every 4 weeks if platelets are 75,000 to 100,000/mm3, and as clinically necessary if platelets are >100,000/mm3. Evaluate pregnancy status prior to use in females of reproductive potential. Monitor for cognitive effects (eg, memory impairment, confusion, amnesia, sleep/speech disorders) and for signs/symptoms of intracranial hemorrhage (particularly in patients with thrombocytopenia, vascular aneurysm, or history of intracranial hemorrhage or cerebrovascular accident within the prior year). Monitor adherence.
The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
Avapritinib is a potent tyrosine kinase inhibitor that blocks PDGFRA and KIT D816V; it targets PDGFRA and PDGFR D842 mutants, as well as KIT exon 11, 11/17, and 17 mutants. Certain PDGFRA and KIT mutations may result in autophosphorylation and constitutive activation of these receptors, which may contribute to tumor and mast cell proliferation. Avapritinib inhibits autophosphorylation of KIT D816V and PDGFRA D842V, which are mutations associated with resistance to approved kinase inhibitors.
Distribution: Vd: GIST (300 mg dose): 1,200 L; systemic mastocytosis (200 mg dose): 1,900 L.
Protein binding: 98.8%.
Metabolism: Primarily hepatic via CYP3A4 and CYP3A5 (major) and CYP2C9 (minor); the formation of the glucuronide metabolite (M690) is primarily catalyzed by UGT1A3.
Half-life elimination: 32 to 57 hours.
Time to peak: 2 to 4 hours.
Excretion: Feces: 70% (11% as unchanged drug); urine: 18% (<1% as unchanged drug).
Clearance: 21.8 L/hour (GIST); 40.3 L/hour (systemic mastocytosis).
Tablets (Ayvakit Oral)
25 mg (per each): $1,408.52
50 mg (per each): $1,408.52
100 mg (per each): $1,408.52
200 mg (per each): $1,408.52
300 mg (per each): $1,408.52
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