avapritinib

High Alert

Unresectable or metastatic gastrointestinal stromal tumor that possesses a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation, including PDGFRA D842V mutations.
Advanced systemic mastocytosis (including aggressive systemic mastocytosis, systemic mastocytosis with an associated hematological neoplasm, and mast cell leukemia).
Indolent systemic mastocytosis.

Action ⬆ ⬇

Tyrosine kinase inhibitor that binds to and inhibits PDGFRA, which contributes to its antitumor activity. It specifically targets tumors that contain PDGFRA and PDGFRA D842 mutants as well as multiple KIT exon 11, 11/17 and 17 mutants.

Therapeutic effects:

Decreased progression of gastrointestinal stromal tumor.
Reduced number of mast cells for patients with advanced systemic mastocytosis.
Reduced symptoms of indolent systemic mastocytosis.

Pharmacokinetics ⬆ ⬇

Absorption: Extent of absorption ↑ with high-fat meals.

Distribution: Extensively distributed to tissues.

Metabolism/Excretion: Primarily metabolized by the liver via the CYP3A4 isoenzyme (and CYP2C9 to a lesser extent). Primarily excreted in feces (70%; 11% as unchanged drug); 18% excreted in urine (primarily as metabolites).

Half-Life: 32–57 hr.

Time/Action Profile ⬆ ⬇

(plasma concentrations)

ROUTE	ONSET	PEAK	DURATION
PO	unknown	2–4 hr	24 hr

Contraind./Precautions ⬆ ⬇

Contraindicated in:

Platelet count <50 x 10⁹/L (patients with advanced systemic mastocytosis and indolent systemic mastocytosis only) (↑ risk of intracranial hemorrhage);
OB: Pregnancy;
Lactation: Lactation.

Use Cautiously in:

Severe renal impairment or end-stage renal disease;
Severe hepatic impairment (↓ dose);
Rep: Women of reproductive potential and men with female partners of reproductive potential;
Pedi: Safety and effectiveness not established in children.

Adv. Reactions/Side Effects ⬆ ⬇

CV: edema, hypertension

Derm: alopecia, hair color changes, rash

EENT: ↑tear production, photosensitivity

Endo: hyperthyroidism, hypothyroidism

F and E: hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia

GI: abdominal pain, constipation, diarrhea, dyspepsia, hyperbilirubinemia, hypoalbuminemia, ↑liver enzymes, nausea, vomiting, GI BLEEDING

GU: acute kidney injury, ↓fertility

Hemat: anemia, leukopenia, neutropenia, thrombocytopenia

Metab: ↓appetite, ↓weight

Neuro: cognitive impairment, dizziness, headache, mood disorders, sleep disorders, taste disturbances, hallucinations, INTRACRANIAL HEMORRHAGE, speech disorders

Resp: dyspnea, pleural effusion

Misc: fatigue, fever

Interactions ⬆ ⬇

Drug-drug:

Strong CYP3A inhibitors, including ketoconazole, or moderate CYP3A inhibitors, including fluconazole, may ↑ levels and risk of toxicity; avoid concurrent use. If concurrent use with moderate CYP3A4 inhibitor unavoidable, ↓ avapritinib dose (for GIST and advanced systemic mastocytosis only).
Strong CYP3A inducers, including rifampin, or moderate CYP3A inducers, including efavirenz, may ↓ levels and effectiveness; avoid concurrent use.

Route/Dosage ⬆ ⬇

Gastrointestinal Stromal Tumor Harboring PDGFRA Exon 18 Mutations

PO (Adults ): 300 mg once daily until disease progression or unacceptable toxicity. Concurrent use of moderate CYP3A inhibitor: 100 mg once daily until disease progression or unacceptable toxicity.

Hepatic Impairment

PO (Adults ): Severe hepatic impairment—200 mg once daily until disease progression or unacceptable toxicity.

Advanced Systemic Mastocytosis

PO (Adults ): 200 mg once daily until disease progression or unacceptable toxicity. Concurrent use of moderate CYP3A inhibitor: 50 mg once daily until disease progression or unacceptable toxicity.

Hepatic Impairment

PO (Adults ): Severe hepatic impairment—100 mg once daily until disease progression or unacceptable toxicity.

Indolent Systemic Mastocytosis

PO (Adults ): 25 mg once daily.

Hepatic Impairment

PO (Adults ): Severe hepatic impairment—25 mg every other day.

Availability ⬆ ⬇

Tablets: 25 mg; 50 mg; 100 mg; 200 mg; 300 mg

Assessment ⬆ ⬇

Monitor for signs and symptoms of intracranial hemorrhage (severe headache, vision problems, severe sleepiness, severe weakness on one side of body) periodically during therapy. If Grade 1 or Grade 2 signs occur, hold dose and resume with 100 mg dose. If Grade 1 or 2 recurs or Grade 3 or Grade 4 occurs, permanently discontinue avapritinib.
Monitor for signs and symptoms of central nervous system adverse reactions (cognitive impairment, dizziness, sleep disorders, mood disorders, speech disorders, hallucinations) periodically during therapy. If Grade 1 symptoms occur, continue at same dose or hold dose until return to baseline or resolution. Resume at same or reduced dose. If Grade 2 or Grade 3 symptoms occur, hold until return to baseline, Grade 1, or resolution. Resume at same or reduced dose. If Grade 4 symptoms occur, discontinue permanently.

Lab Test Considerations:

Verify a negative pregnancy test before starting avapritinib.
- May cause ↓ hemoglobin, leukocytes, neutrophils, platelets and ↑ INR and activated partial thromboplastin time.
- May cause ↑ bilirubin, AST, ALT, alkaline phosphatase, serum creatinine and ↓ phosphate, potassium, albumin, magnesium, and sodium.
- Advanced Systemic Mastocytosis: Monitor platelet count every 2 wk for 8 wk. After 8 wk of therapy, if platelet count <75 x 10⁹/L, monitor platelet counts every 2 wk (or more frequently as indicated). If platelet counts are between 75 and 100 x 10⁹/L, monitor platelet count every 4 wk. If platelet counts>100 x 10⁹/L, monitor platelet counts as clinically indicated. If platelet count < 50 x 10⁹/L, hold therapy and reduce dose of avapritinib.

Implementation ⬆ ⬇

PO: Administer once daily on an empty stomach, at least 1 hr before and 2 hr after a meal.

Patient/Family Teaching ⬆ ⬇

Instruct patient to take avapritinib as directed. Take missed doses as soon as possible, but not within 8 hr of next dose. Do not take an additional dose if vomiting occurs after dose; continue with next scheduled dose.
May cause cognitive impairment and dizziness. Instruct patient to avoid driving and other activities requiring alertness until response to medication is known.
Advise patient to notify health care professional if signs and symptoms of intracranial hemorrhage or central nervous system side effects (forgetfulness, confusion, getting lost, trouble thinking, drowsiness, dizziness, trouble sleeping, word finding problems, seeing objects or hearing things that are not there, change in mood or behavior) occur.
Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications.
Discuss the possibility of hair loss with patient. Explore methods of coping.
Rep: May cause fetal harm. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during and for at least 6 wk after last dose. Advise women to avoid breastfeeding during and for 2 wk following last dose. May impair male and female fertility.

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Pronunciation ⬇

Classifications ⬆ ⬇

Indications ⬆ ⬇

Action ⬆ ⬇

Pharmacokinetics ⬆ ⬇

Time/Action Profile ⬆ ⬇

Contraind./Precautions ⬆ ⬇

Adv. Reactions/Side Effects ⬆ ⬇

Interactions ⬆ ⬇

Route/Dosage ⬆ ⬇

Availability ⬆ ⬇

Assessment ⬆ ⬇

Implementation ⬆ ⬇

Patient/Family Teaching ⬆ ⬇

Evaluation/Desired Outcomes ⬆ ⬇

US Brand Names ⬆