ripretinib (Rx)

Brand and Other Names:Qinlock
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

tablet

  • 50mg

Gastrointestinal Stromal Tumors

Indicated for advanced gastrointestinal stromal tumor (GIST) in adults previously treated with 3 or more kinase inhibitors, including imatinib

150 mg PO qDay

Continue until disease progression or unacceptable toxicity

Dosage Modifications

Dose reduction recommendations

  • Reduce to 100 mg qDay
  • Unable to tolerate 100 mg/day: Permanently discontinue

Left ventricular systolic dysfunction

  • Grade 3 or 4: Permanently discontinue

Palmoplantar erythrodysesthesia syndrome (PPES)

  • Grade 2
    • Withhold until Grade ≤1 or baseline; resume at the same dose if resolved within 7 days; otherwise, resume at reduced dose
    • Consider re-escalating dose if maintained at Grade ≤1 or baseline for at least 28 days
    • If PPES recurs, withhold until Grade ≤1 or baseline and then resume at a reduced dose regardless of time to improvement
  • Grade 3
    • Withhold for at least 7 days or until Grade ≤1or baseline (maximum 28 days) and then resume at reduced dose
    • Consider re-escalating dose if maintained at Grade ≤1 for at least 28 days

Hypertension

  • Grade 3
    • Symptomatic: Withhold until symptoms resolve and blood pressure (BP) is controlled; resume at the same dose if BP is controlled to Grade ≤1 or baseline; otherwise, resume at reduced dose
    • Grade 3 hypertension recurs: Withhold until symptoms resolve and BP is controlled; resume at reduced dose
  • Grade 4
    • Permanently discontinue

Arthralgia or myalgia

  • Grade 2
    • Withhold until Grade ≤1 or baseline; resume at the same dose if resolved within 7 days; otherwise, resume at reduced dose
    • Consider re-escalating dose if maintained at Grade ≤1 or baseline for at least 28 days
    • If arthralgia or myalgia recurs, withhold until Grade ≤1 or baseline and then resume at a reduced dose regardless of time to improvement
  • Grade 3
    • Withhold for at least 7 days or until Grade ≤1 or baseline (maximum 28 days) and then resume at reduced dose
    • Consider re-escalating dose if maintained at Grade ≤1 or baseline for at least 28 days

Other adverse reactions

  • Grade 3 or 4
    • Withhold for at least 7 days or until Grade ≤1 or baseline (maximum 28 days) and then resume at reduced dose; otherwise permanently discontinue
    • Consider re-escalating dose if maintained at Grade ≤1 for at least 28 days
    • If Grade 3 or 4 recurs, permanently discontinue

Renal impairment

  • Mild-to-moderate (CrCl 30 to <90 mL/min): No clinically significant differences in the pharmacokinetics of ripretinib were observed
  • Severe (CrCl 15 to 29 mL/min): Pharmacokinetics of ripretinib have not been studied

Hepatic impairment

  • Mild (total bilirubin [TB] ≤ULN and AST >ULN or TB 1-1.5x ULN and any AST): No dose adjustment necessary
  • Moderate or severe: Recommended dosage has not been established

Dosing Considerations

Verify pregnancy status of females of reproductive potential before initiating

Safety and efficacy not established

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Interactions

Interaction Checker

and ripretinib

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    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

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            Contraindicated (0)

              Serious - Use Alternative (21)

              • amobarbital

                amobarbital will decrease the level or effect of ripretinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration with a strong CYP3A inhibitor will decrease systemic exposure to ripretinib and its active metabolite (DP-5439), which may decrease risk of adverse reactions.

              • apalutamide

                apalutamide will decrease the level or effect of ripretinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration with a strong CYP3A inhibitor will decrease systemic exposure to ripretinib and its active metabolite (DP-5439), which may decrease risk of adverse reactions.

              • bosentan

                bosentan will decrease the level or effect of ripretinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration with a strong CYP3A inhibitor will decrease systemic exposure to ripretinib and its active metabolite (DP-5439), which may decrease risk of adverse reactions.

              • carbamazepine

                carbamazepine will decrease the level or effect of ripretinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration with a strong CYP3A inhibitor will decrease systemic exposure to ripretinib and its active metabolite (DP-5439), which may decrease risk of adverse reactions.

              • dabrafenib

                dabrafenib will decrease the level or effect of ripretinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration with a strong CYP3A inhibitor will decrease systemic exposure to ripretinib and its active metabolite (DP-5439), which may decrease risk of adverse reactions.

              • efavirenz

                efavirenz will decrease the level or effect of ripretinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration with a strong CYP3A inhibitor will decrease systemic exposure to ripretinib and its active metabolite (DP-5439), which may decrease risk of adverse reactions.

              • enzalutamide

                enzalutamide will decrease the level or effect of ripretinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration with a strong CYP3A inhibitor will decrease systemic exposure to ripretinib and its active metabolite (DP-5439), which may decrease risk of adverse reactions.

              • etravirine

                etravirine will decrease the level or effect of ripretinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration with a strong CYP3A inhibitor will decrease systemic exposure to ripretinib and its active metabolite (DP-5439), which may decrease risk of adverse reactions.

              • fosphenytoin

                fosphenytoin will decrease the level or effect of ripretinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration with a strong CYP3A inhibitor will decrease systemic exposure to ripretinib and its active metabolite (DP-5439), which may decrease risk of adverse reactions.

              • lumacaftor/ivacaftor

                lumacaftor/ivacaftor will decrease the level or effect of ripretinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration with a strong CYP3A inhibitor will decrease systemic exposure to ripretinib and its active metabolite (DP-5439), which may decrease risk of adverse reactions.

              • mitotane

                mitotane will decrease the level or effect of ripretinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration with a strong CYP3A inhibitor will decrease systemic exposure to ripretinib and its active metabolite (DP-5439), which may decrease risk of adverse reactions.

              • nafcillin

                nafcillin will decrease the level or effect of ripretinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration with a strong CYP3A inhibitor will decrease systemic exposure to ripretinib and its active metabolite (DP-5439), which may decrease risk of adverse reactions.

              • pentobarbital

                pentobarbital will decrease the level or effect of ripretinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration with a strong CYP3A inhibitor will decrease systemic exposure to ripretinib and its active metabolite (DP-5439), which may decrease risk of adverse reactions.

              • phenobarbital

                phenobarbital will decrease the level or effect of ripretinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration with a strong CYP3A inhibitor will decrease systemic exposure to ripretinib and its active metabolite (DP-5439), which may decrease risk of adverse reactions.

              • phenytoin

                phenytoin will decrease the level or effect of ripretinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration with a strong CYP3A inhibitor will decrease systemic exposure to ripretinib and its active metabolite (DP-5439), which may decrease risk of adverse reactions.

              • primidone

                primidone will decrease the level or effect of ripretinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration with a strong CYP3A inhibitor will decrease systemic exposure to ripretinib and its active metabolite (DP-5439), which may decrease risk of adverse reactions.

              • rifabutin

                rifabutin will decrease the level or effect of ripretinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration with a strong CYP3A inhibitor will decrease systemic exposure to ripretinib and its active metabolite (DP-5439), which may decrease risk of adverse reactions.

              • rifampin

                rifampin will decrease the level or effect of ripretinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration with a strong CYP3A inhibitor will decrease systemic exposure to ripretinib and its active metabolite (DP-5439), which may decrease risk of adverse reactions.

              • rifapentine

                rifapentine will decrease the level or effect of ripretinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration with a strong CYP3A inhibitor will decrease systemic exposure to ripretinib and its active metabolite (DP-5439), which may decrease risk of adverse reactions.

              • secobarbital

                secobarbital will decrease the level or effect of ripretinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration with a strong CYP3A inhibitor will decrease systemic exposure to ripretinib and its active metabolite (DP-5439), which may decrease risk of adverse reactions.

              • St John's Wort

                St John's Wort will decrease the level or effect of ripretinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration with a strong CYP3A inhibitor will decrease systemic exposure to ripretinib and its active metabolite (DP-5439), which may decrease risk of adverse reactions.

              Monitor Closely (32)

              • armodafinil

                armodafinil will decrease the level or effect of ripretinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. If coadministration cannot be avoided, increase dosing frequency from recommended dose of 150 mg once daily to 150 mg twice daily during co-administration period; monitor for clinical response and tolerability

              • atazanavir

                atazanavir will increase the level or effect of ripretinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration with a strong CYP3A inhibitor will increase systemic exposure to ripretinib and its active metabolite (DP-5439), which may increase risk of adverse reactions.

              • bexarotene

                bexarotene will decrease the level or effect of ripretinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. If coadministration cannot be avoided, increase dosing frequency from recommended dose of 150 mg once daily to 150 mg twice daily during co-administration period; monitor for clinical response and tolerability

              • brigatinib

                brigatinib will decrease the level or effect of ripretinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. If coadministration cannot be avoided, increase dosing frequency from recommended dose of 150 mg once daily to 150 mg twice daily during co-administration period; monitor for clinical response and tolerability

              • chloramphenicol

                chloramphenicol will increase the level or effect of ripretinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration with a strong CYP3A inhibitor will increase systemic exposure to ripretinib and its active metabolite (DP-5439), which may increase risk of adverse reactions.

              • clarithromycin

                clarithromycin will increase the level or effect of ripretinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration with a strong CYP3A inhibitor will increase systemic exposure to ripretinib and its active metabolite (DP-5439), which may increase risk of adverse reactions.

              • clobazam

                clobazam will decrease the level or effect of ripretinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. If coadministration cannot be avoided, increase dosing frequency from recommended dose of 150 mg once daily to 150 mg twice daily during co-administration period; monitor for clinical response and tolerability

              • cobicistat

                cobicistat will increase the level or effect of ripretinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration with a strong CYP3A inhibitor will increase systemic exposure to ripretinib and its active metabolite (DP-5439), which may increase risk of adverse reactions.

              • conivaptan

                conivaptan will increase the level or effect of ripretinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration with a strong CYP3A inhibitor will increase systemic exposure to ripretinib and its active metabolite (DP-5439), which may increase risk of adverse reactions.

              • darunavir

                darunavir will increase the level or effect of ripretinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration with a strong CYP3A inhibitor will increase systemic exposure to ripretinib and its active metabolite (DP-5439), which may increase risk of adverse reactions.

              • elagolix

                elagolix will decrease the level or effect of ripretinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. If coadministration cannot be avoided, increase dosing frequency from recommended dose of 150 mg once daily to 150 mg twice daily during co-administration period; monitor for clinical response and tolerability

              • encorafenib

                encorafenib will decrease the level or effect of ripretinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. If coadministration cannot be avoided, increase dosing frequency from recommended dose of 150 mg once daily to 150 mg twice daily during co-administration period; monitor for clinical response and tolerability

              • eslicarbazepine acetate

                eslicarbazepine acetate will decrease the level or effect of ripretinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. If coadministration cannot be avoided, increase dosing frequency from recommended dose of 150 mg once daily to 150 mg twice daily during co-administration period; monitor for clinical response and tolerability

              • grapefruit

                grapefruit will increase the level or effect of ripretinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration with a strong CYP3A inhibitor will increase systemic exposure to ripretinib and its active metabolite (DP-5439), which may increase risk of adverse reactions.

              • idelalisib

                idelalisib will increase the level or effect of ripretinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration with a strong CYP3A inhibitor will increase systemic exposure to ripretinib and its active metabolite (DP-5439), which may increase risk of adverse reactions.

              • indinavir

                indinavir will increase the level or effect of ripretinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration with a strong CYP3A inhibitor will increase systemic exposure to ripretinib and its active metabolite (DP-5439), which may increase risk of adverse reactions.

              • isoniazid

                isoniazid will increase the level or effect of ripretinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration with a strong CYP3A inhibitor will increase systemic exposure to ripretinib and its active metabolite (DP-5439), which may increase risk of adverse reactions.

              • itraconazole

                itraconazole will increase the level or effect of ripretinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration with a strong CYP3A inhibitor will increase systemic exposure to ripretinib and its active metabolite (DP-5439), which may increase risk of adverse reactions.

              • ketoconazole

                ketoconazole will increase the level or effect of ripretinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration with a strong CYP3A inhibitor will increase systemic exposure to ripretinib and its active metabolite (DP-5439), which may increase risk of adverse reactions.

              • lorlatinib

                lorlatinib will decrease the level or effect of ripretinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. If coadministration cannot be avoided, increase dosing frequency from recommended dose of 150 mg once daily to 150 mg twice daily during co-administration period; monitor for clinical response and tolerability

              • mifepristone

                mifepristone will increase the level or effect of ripretinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration with a strong CYP3A inhibitor will increase systemic exposure to ripretinib and its active metabolite (DP-5439), which may increase risk of adverse reactions.

              • modafinil

                modafinil will decrease the level or effect of ripretinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. If coadministration cannot be avoided, increase dosing frequency from recommended dose of 150 mg once daily to 150 mg twice daily during co-administration period; monitor for clinical response and tolerability

              • nefazodone

                nefazodone will increase the level or effect of ripretinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration with a strong CYP3A inhibitor will increase systemic exposure to ripretinib and its active metabolite (DP-5439), which may increase risk of adverse reactions.

              • nelfinavir

                nelfinavir will increase the level or effect of ripretinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration with a strong CYP3A inhibitor will increase systemic exposure to ripretinib and its active metabolite (DP-5439), which may increase risk of adverse reactions.

              • posaconazole

                posaconazole will increase the level or effect of ripretinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration with a strong CYP3A inhibitor will increase systemic exposure to ripretinib and its active metabolite (DP-5439), which may increase risk of adverse reactions.

              • ritonavir

                ritonavir will increase the level or effect of ripretinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration with a strong CYP3A inhibitor will increase systemic exposure to ripretinib and its active metabolite (DP-5439), which may increase risk of adverse reactions.

              • saquinavir

                saquinavir will increase the level or effect of ripretinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration with a strong CYP3A inhibitor will increase systemic exposure to ripretinib and its active metabolite (DP-5439), which may increase risk of adverse reactions.

              • sotorasib

                sotorasib will decrease the level or effect of ripretinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. If coadministration cannot be avoided, increase dosing frequency from recommended dose of 150 mg once daily to 150 mg twice daily during co-administration period; monitor for clinical response and tolerability

              • stiripentol

                stiripentol will increase the level or effect of ripretinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration with a strong CYP3A inhibitor will increase systemic exposure to ripretinib and its active metabolite (DP-5439), which may increase risk of adverse reactions.

              • telotristat ethyl

                telotristat ethyl will decrease the level or effect of ripretinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. If coadministration cannot be avoided, increase dosing frequency from recommended dose of 150 mg once daily to 150 mg twice daily during co-administration period; monitor for clinical response and tolerability

              • tipranavir

                tipranavir will increase the level or effect of ripretinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration with a strong CYP3A inhibitor will increase systemic exposure to ripretinib and its active metabolite (DP-5439), which may increase risk of adverse reactions.

              • voriconazole

                voriconazole will increase the level or effect of ripretinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration with a strong CYP3A inhibitor will increase systemic exposure to ripretinib and its active metabolite (DP-5439), which may increase risk of adverse reactions.

              Minor (0)

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                Adverse Effects

                >10%

                All grades

                • Alopecia (52%)
                • Fatigue (42%)
                • Nausea (39%)
                • Abdominal pain (36%)
                • Increased aPTT (35%)
                • Constipation (34%)
                • Myalgia (32%)
                • Increased lipase (32%)
                • Diarrhea (28%)
                • Decreased appetite (27%)
                • Decreased phosphate (26%)
                • Increased triglycerides (26%)
                • Decreased calcium (23%)
                • Increased blood bilirubin (22%)
                • PPES (21%)
                • Increased CPK (21%)
                • Increased INR (21%)
                • Vomiting (21%)
                • Decreased weight (19%)
                • Headache (19%)
                • Arthralgia (18%)
                • Decreased sodium (17%)
                • Peripheral edema (17%)
                • Increased creatinine (16%)
                • Muscle spasms (15%)
                • Hypertension (14%)
                • Dyspnea (13%)
                • Increased serum amylase (13%)
                • Dry skin (13%)
                • Asthenia (13%)
                • Increased ALT (12%)
                • Stomatitis (11%)
                • Pruritus (11%)

                1-10%

                All grades

                • Decreased neutrophil count (10%)

                Grade 3-4

                • Abdominal pain (7%)
                • Hypertension (7%)
                • Increased lipase (7%)
                • Decreased phosphate (4.9%)
                • Increased INR (3.8%)
                • Fatigue (3.5%)
                • Nausea (3.5%)
                • Vomiting (3.5%)
                • Decreased sodium (2.4%)
                • Increased triglycerides (2.4%)
                • Peripheral edema (1.2%)
                • Asthenia (1.2%)
                • Constipation (1.2%)
                • Diarrhea (1.2%)
                • Decreased appetite (1.2%)
                • Myalgia (1.2%)
                • Increased serum amylase (1.2%)
                • Increased ALT (1.2%)
                • Increased CPK (1.2%)
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                Warnings

                Contraindications

                None

                Cautions

                PPES reported

                Fetal harm may occur when administered to pregnant females

                Wound healing complications

                • Impaired wound healing complications can occur in patients who receive drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway; use may adversely affect wound healing
                • Withhold for at least 1 week before elective surgery; do not administer for at least 2 weeks following major surgery and until adequate wound healing
                • Safety of resumption after resolution of wound healing complications has not been established
                • Primary cutaneous malignancies H4
                • Cutaneous squamous cell carcinoma occurred with a median time to event of 4.6 months
                • Melanoma and keratoacanthoma also reported
                • Perform dermatologic evaluations when initiating and routinely during treatment
                • Manage suspicious skin lesions with excision and dermatopathologic evaluation; continue at the same dose

                Cardiac dysfunction

                • Cardiac dysfunction (including cardiac failure, acute left ventricular failure, diastolic dysfunction, and ventricular hypertrophy) occurred
                • Grade 3 decreased ejection fraction (EF) reported
                • Safety has not been assessed in patients with a baseline EF <50%
                • Assess EF by echocardiogram or multigated acquisition scan before initiating and during treatment, as clinically indicated

                Drug interaction overview

                • Ripretinib and DP-5439 (active metabolite) inhibit CYP2C8, P-gp (P-glycoprotein), and BCRP (breast cancer resistance protein)
                • DP-5439 is a substrate of P-gp and BCRP
                • DP-5439 inhibits MATE1 (multidrug and toxin extrusion protein 1)
                • Strong CYP3A inhibitors
                  • Coadministration with a strong CYP3A inhibitor increases ripretinib and DP-5439 systemic exposure, which may increase risk of adverse reactions
                  • Closely monitor for adverse reactions
                • Moderate or strong CYP3A inducers
                  • Avoid coadministration
                  • Coadministration with a moderate or strong CYP3A inducer may decrease ripretinib and DP-5439 systemic exposure, which may decrease antitumor activity
                  • If coadministration with a moderate CYP3A inducer cannot be avoided, increase dosing frequency from recommended dose of 150 mg once daily to 150 mg twice daily during co-administration period; monitor for clinical response and tolerability
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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 pregnant females

                No data available on use in pregnant females to inform a drug-associated risk

                Verify pregnancy status of females of reproductive potential before initiation

                Animal data

                • Administration to pregnant rats and rabbits during organogenesis resulted in malformations primarily associated with the cardiovascular and skeletal systems, anatomic variations, reduced fetal body weight, and increased postimplantation loss at maternal exposures that were approximately equal to 150 mg
                • Advise pregnant females of the potential risk to a fetus

                Contraception

                • Females of reproductive potential: Use effective contraception during treatment and for at least 1 week after the final dose
                • Males with female partners of reproductive potential: Use effective contraception during treatment and for at least 1 week after the final dose

                Infertility

                • Based on findings from animal studies, fertility may be impaired in males of reproductive potential

                Lactation

                No data available

                Advise females not to breastfeed during treatment and for at least 1 week after 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

                Broad-spectrum inhibitor or proto-oncogene receptor tyrosine kinase (KIT) and platelet derived growth factor receptor-A (PDGFRA), including wild type, primary, and secondary mutations

                Also, inhibits other kinases in vitro (eg, PDGFRB, TIE2, VEGFR2, BRAF)

                Absorption

                Steady-state achieved in 14 days

                Peak plasma concentration

                • Ripretinib: 761 ng/mL
                • DP-5439 (active metabolite): 804 ng/mL

                Peak plasma time

                • Ripretinib: 4 hr
                • DP-5439: 15.6 hr

                AUC H4

                • Ripretinib: 5678 ng·hr/mL
                • DP-5439: 7138 ng·hr/mL

                Distribution

                Vd (steady-state)

                • Ripretinib: 307 L
                • DP-5439: 507 L

                Protein bound

                • Human serum albumin
                  • Ripretinib: 99.8%
                  • DP-5439: 99.7%
                • Alpha-1 acid glycoprotein
                  • Ripretinib: 99.4%
                  • DP-5439: >99.8%

                Metabolism

                Major pathway: CYP3A4 (ripretinib and DP-5439 [active metabolite])

                Minor pathway

                • Ripretinib: CYP2C8 and CYP2D6
                • DP-5439: CYP2C8, CYP2E1, and CYP2D6

                Elimination

                Excretion

                • Ripretinib: Feces (34%); urine (0.02%)
                • DP-5439: Feces (6%); urine (0.1%)
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                Administration

                Oral Administration

                May take with or without food at the same time each day

                Swallow tablets whole

                Missed dose <8 hr passed since missed scheduled dose: May take missed dose

                Vomited dose: Do not to take an additional dose and continue with next scheduled dose

                Storage

                Dispense in original container only

                Store in the original container with the desiccant to protect from moisture and light

                Replace cap securely each time after opening; do not discard desiccant

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

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                Patient Handout

                A Patient Handout is not currently available for this monograph.
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                Formulary

                FormularyPatient Discounts

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                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
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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.