avapritinib (Rx)

Brand and Other Names:Ayvakit
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

tablet

  • 100mg
  • 200mg
  • 300mg

Gastrointestinal Stromal Tumors

Indicated for adults with unresectable or metastatic gastrointestinal stromal tumor (GIST) harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation, including PDGFRA D842V mutation

300 mg PO qDay

Continue until disease progression or unacceptable toxicity

Dosage Modifications

Dosage modifications for adverse reactions

  • First dose reduction: 200 mg qDay
  • Second dose reduction: 100 mg qDay
  • Permanently discontinue in patients who are unable to tolerate a 100-mg dose

Intracranial hemorrhage

  • First occurrence of Grade 1 or 2: Withhold until resolution; resume at reduced dose
  • Subsequent occurrence of Grade 1 or 2: Permanently discontinue
  • Grade 3 or 4: Permanently discontinue

CNS effects

  • Grade 1: Continue dose at the same dose or withhold until improvement to baseline or resolution; resume at same dose or reduced dose
  • Grade 2 or 3: Withhold until improvement to baseline, Grade 1, or resolution; resume at same dose or reduced dose
  • Grade 4: Permanently discontinue

Other adverse reactions

  • Grade 3 or 4: Withhold until improvement to Grade ≤2, or resolution; resume at same dose or reduced dose, as clinically appropriate

Concomitant use of strong or moderate CYP3A4 inhibitors

  • Strong or moderate CYP3A4 inhibitors: Avoid use; if concomitant use with a moderate CYP3A inhibitor is unavoidable, reduce starting dose of avapritinib to 100 mg qDay

Renal impairment

  • Mild-to-moderate (CrCl 30 to 90 mL/mL): No dosage adjustment necessary
  • Severe or end-stage renal disease (CrCl <30 mL/min): Recommended dose has not been established

Hepatic impairment

  • Mild-to-moderate (total bilirubin ≤3x ULN and any AST): No dosage adjustment necessary
  • Severe (total bilirubin >3x ULN and any AST): Recommended dose has not been established

Dosing Considerations

Select patients for treatment based on the presence of a PDGFRA exon 18 mutation

An FDA-approved test for the detection of exon 18 mutations is not currently available

Safety and efficacy not established

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Interactions

Interaction Checker

and avapritinib

No Results

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    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            Adverse Effects

            >10%

            All grades

            • Decreased hemoglobin (81%)
            • Edema (72%)
            • Increased bilirubin (69%)
            • Nausea (64%)
            • Decreased leukocytes (62%)
            • Fatigue (61%)
            • Increased AST (51%)
            • Decreased phosphate (49%)
            • Cognitive impairment (48%)
            • Decreased neutrophils (43%)
            • Vomiting (38%)
            • Decreased appetite (38%)
            • Diarrhea (37%)
            • Decreased potassium (34%)
            • Increased lacrimation (33%)
            • Abdominal pain (31%)
            • Decreased albumin (31%)
            • Decreased magnesium (29%)
            • Increased creatinine (29%)
            • Decreased sodium (28%)
            • Decreased platelets (27%)
            • Increased INR (24%)
            • Constipation (23%)
            • Rash (23%)
            • Dizziness (22%)
            • Hair color changes (21%)
            • Increased ALT (19%)
            • Headache (17%)
            • Dyspnea (17%)
            • Sleep disorders (16%)
            • Taste effects (15%)
            • Pyrexia (14%)
            • Increased alkaline phosphatase (14%)
            • Mood disorders (13%)
            • Alopecia (13%)
            • Decreased weight (13%)
            • Increased activated partial thromboplastin time (13%)
            • Pleural effusion (12%)

            Grade ≥3

            • Decreased hemoglobin (28%)
            • Decreased phosphate (13%)

            1-10%

            All grades

            • Hypertension (8%)
            • Thyroid disorders (hyperthyroid, hypothyroid) (3%)
            • Palmar-plantar erythrodysesthesia (1%)

            Grade≥3

            • Fatigue (9%)
            • Increased bilirubin (9%)
            • Abdominal pain (6%)
            • Decreased neutrophils (6%)
            • Decreased potassium (6%)
            • Decreased sodium (7%)
            • Decreased leukocytes (5%)
            • Diarrhea (4.9%)
            • Cognitive impairment (4.9%)
            • Decreased appetite (2.9%)
            • Nausea (2.5%)
            • Dyspnea (2.5%)
            • Rash (2.1%)
            • Vomiting (2%)
            • Edema (2%)
            • Pleural effusion (2%)
            • Decreased albumin (2%)
            • Constipation (1.5%)
            • Increased AST (1.5%)
            • Mood disorders (1%)
            • Decreased weight (1%)
            • Decreased magnesium (1%)
            • Increased alkaline phosphatase (1%)

            <1%

            Grade ≥3

            • Increased INR (0.6%)
            • Pyrexia (0.5%)
            • Dizziness (0.5%)
            • Headache (0.5%)
            • Hair color changes (0.5%)
            • Decreased platelets (0.5%)
            • Increased ALT (0.5%)
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            Warnings

            Contraindications

            None

            Cautions

            Intracranial hemorrhage (eg, subdural hematoma, intracranial hemorrhage, cerebral hemorrhage) occurred

            A broad spectrum of CNS adverse reactions were reported; these include cognitive impairment, dizziness, sleep disorders, mood disorders, speech disorders, and hallucinations

            Based on findings from animal studies and its mechanism of action, fetal harm can occur when administered to pregnant women

            Drug interaction overview

            • Avapritinib is a CYP3A4 and a CYP2C9 substrate
            • Strong and moderate CYP3A inhibitors
              • Coadministration with a strong or moderate CYP3A inhibitor increases avapritinib plasma concentrations, which may increase the incidence and severity of adverse reactions of avapritinib
            • Strong and moderate CYP3A inducers
              • Coadministration with a strong or moderate CYP3A inducer decreases avapritinib plasma concentrations, which may decrease efficacy of avapritinib
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            Pregnancy & Lactation

            Pregnancy

            Based on findings from animal studies and its mechanism of action, fetal harm may occur when administered to a pregnant woman

            No data available on use in pregnant women

            Verify pregnancy status of females of reproductive potential before initiation

            Contraception

            • Females of reproductive potential: Use effective contraception during treatment and for 6 weeks after the final dose
            • Males with female partners of reproductive potential: Use effective contraception during treatment and for 6 weeks after the final dose

            Infertility

            • Based on findings from animal studies, may impair fertility for both males and females

            Animal studies H4

            • Oral administration of avapritinib to pregnant animals during organogenesis was teratogenic and embryotoxic in rats at exposure levels ~2.7 times the human exposure based on AUC at the 300-mg dose
            • Advise pregnant women of the potential risk to a fetus

            Lactation

            There are no data on the presence of avapritinib or its metabolites in human milk or the effects of avapritinib on the breastfed child or milk production

            Advise women not to breastfeed during treatment and for 2 weeks following the final dose

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Tyrosine kinase inhibitor binds to and inhibits specific mutant forms of PDGFRα and c-Kit, including the PDGFRα D842V mutant and various KIT exon 17 mutants

            This results in the inhibition of PDGFRa- and c-Kit-mediated signal transduction pathways and the inhibition of proliferation in tumor cells that express these PDGFRa and c-Kit mutants

            Absorption

            Peak plasma concentration: 813 ng/mL

            Peak plasma time: 2-4 hr

            AUC: 15400 hr⋅ng/mL

            Steady-state was reached by day 15

            Effects of food

            • Peak plasma concentration increased by 59% and AUC increased by 29% when administered with a high-calorie, high-fat meal (~909 calories, 58 grams carbohydrate, 56 grams fat, and 43 grams protein) compared with the fasted state

            Distribution

            Vd: 1200 L

            Blood-to-plasma ratio: 0.95

            Metabolism

            Primarily metabolized by CYP3A4 and to a lesser extent by CYP2C9 into unchanged drug and its metabolites M690 (hydroxy glucuronide) and M499 (oxidative deamination)

            Following oral administration of 300-mg dose, the steady-state AUC of M499 is ~80% of the AUC of avapritinib

            M499 is not likely to contribute to efficacy at the recommended dose of avapritinib

            Elimination

            Half-life: 32-57 hr

            Excretion

            • Feces (70% [11% unchanged])
            • Urine (18% [0.23% unchanged])
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            Administration

            Oral Administration

            Administer on an empty stomach, at least 1 hr before and 2 hr after a meal

            Missed dose

            • Do not make up for a missed dose within 8 hr of the next scheduled dose
            • Do not take an additional dose if vomiting occurs after administration; continue with the next scheduled dose

            Storage

            Store at 20-25ºC (68-77ºF); excursions are permitted to 15-30ºC (59-86ºF)

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            Images

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            Formulary

            FormularyPatient Discounts

            Adding plans allows you to compare formulary status to other drugs in the same class.

            To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.

            Adding plans allows you to:

            • View the formulary and any restrictions for each plan.
            • Manage and view all your plans together – even plans in different states.
            • Compare formulary status to other drugs in the same class.
            • Access your plan list on any device – mobile or desktop.

            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
            ST Step Therapy
            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
            OR Other Restrictions
            Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.