General

High Alert Medication: This medication bears a heightened risk of causing significant patient harm when it is used in error.

Genetic Implications:

Pronunciation:
a-va-pri-ti-nib

Trade Name(s)

• Ayvakit

Ther. Class.

antineoplastics

Pharm. Class.

kinase inhibitors

platelet-derived growth factor receptor alpha blockers

Indications

•  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 Effect(s):

• 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 and 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)

Contraindication/Precautions

Contraindicated in:

• Platelet count <50 × 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.

Adverse 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

Metabolic: ↓ 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

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

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.
• May ↑ levels and risk of thromboembolism with  ethinyl estradiol-containing contraceptives.

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 CNS 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 ↓ dose.  If Grade 2 or Grade 3 symptoms occur,  hold dose until return to Grade ≤1. Resume at same or ↓ dose.  If Grade 4 symptoms occur, permanently discontinue avapritinib.

Lab Test Considerations:

Verify a negative pregnancy test before starting therapy.

• May ↓ hemoglobin, leukocytes, neutrophils, and platelets and ↑ INR and activated partial thromboplastin time.
• May ↑ bilirubin, AST, ALT, alkaline phosphatase, and 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 platelets <75 × 10⁹  /L,  monitor platelets every 2 wk (or more frequently as indicated).  If platelet are 75–100 × 10⁹ /L,  monitor platelets every 4 wk.  If platelets >100 × 10⁹ /L,  monitor platelets as clinically indicated.  If platelets < 50 × 10⁹ /L,  hold therapy and ↓ dose.

Implementation

• Antiemetics may be recommended to prevent nausea and vomiting.
• PO Administer once daily on an empty stomach, >1 hr before and 2 hr after a meal.

Patient/Family Teaching

• Explain purpose and side effects of medication to patient. Advise patient to read  Patient Information  before starting therapy. Instruct patient to take 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.
• 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.
• 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 CNS 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.
• Discuss the possibility of hair loss with patient. Explore methods of coping.
• Rep:  May cause fetal harm. Advise women of reproductive potential and men with female partners of reproductive potential to use effective contraception during and for >6 wk after last dose. Advise patient to use nonhormonal contraceptive or contraceptive that does not contain estrogen due to risk of blood clots. If concurrent use unavoidable, use contraceptive containing ≤20 mcg of ethinyl estradiol. Advise women to avoid breastfeeding during therapy and for 2 wk following last dose. May impair fertility.

Evaluation/Desired Outcomes

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