Qinlock (ripretinib)

When dosage modification is necessary, the dosage of ripretinib should be reduced to 100 mg once daily; however, if a dosage of 100 mg once daily is not tolerated, ripretinib should be permanently discontinued.

Ripretinib is administered orally once daily without regard to meals at the same time each day. The tablets should be swallowed whole.

If a dose of ripretinib is missed by <8 hours, administer missed dose as soon as possible. If a dose is missed by >8 hours or if a dose is vomited, skip the missed or vomited dose and take the next dose at the regularly scheduled time.

No dosing information is available for this tab.

Ripretinib is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4 and, to a lesser extent, by CYP2C8 and CYP2D6 to its equally active metabolite DP-5439. DP-5439 is metabolized principally by CYP3A4 and, to a lesser extent, by CYP isoenzymes 2C8, 2E1, and 2D6.

In vitro, ripretinib and DP-5439 inhibit CYP2C8, but do not induce CYP isoenzymes 1A2, 2B6, or 3A4.

In vitro, ripretinib is an inhibitor of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). DP-5439 inhibits BCRP and multidrug and toxic compound extrusion protein (MATE) 1 and is a substrate of P-gp and BCRP.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Ripretinib/Strong Cyp3a4 Inducers

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of ripretinib via this pathway. Ripretinib and the active metabolite DP-5439 contribute to anticancer activity. CYP3A4 is the primary metabolism pathway for both ripretinib and the active metabolite DP-5439.(1)

CLINICAL EFFECTS: Concurrent or recent use of strong CYP3A4 inducers may alter the clinical effectiveness of ripretinib.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Avoid the concurrent use of ripretinib with strong CYP3A4 inducers.(1) When possible, select alternative agents in place of the strong CYP3A4 inducer. Monitor patients receiving concurrent therapy for reduced efficacy. The Australian and UK manufacturers of ripretinib state if co-administration of a strong CYP3A4 inducer cannot be avoided, the dose of ripretinib can be increased from 150 mg once daily to 150 mg twice daily. Co-administration of ripretinib with a strong CYP3A4 inducer must be balanced against a risk of reduced efficacy due to reduced exposure. Monitor for clinical response and tolerability.(2,3) If the strong CYP3A4 inducer is discontinued, reduce the dose of ripretinib back to 150 mg once daily 14 days after discontinuation of the strong CYP3A4 inducer. If a dose of ripretinib is missed (in patients taking twice daily dosing): -If less than 4 hours have passed since missed dose, patient should take the dose as soon as possible and then take the next dose at the regularly scheduled time. -If more than 4 hours have passed since missed dose, patient should skip the missed dose and then take the next dose at the regularly scheduled time.(2,3)

DISCUSSION: The primary metabolism pathway for ripretinib and DP-5439 is via CYP3A4.(1) In an interaction study of rifampin (a strong CYP3A inducer) and ripretinib, concurrent use decreased ripretinib concentration maximum (Cmax) by 18% and area-under-curve (AUC) by 61%, as well as decreased the active metabolite DP-5439 AUC by 57% and increased Cmax by 37%.(1) In an interaction study of efavirenz (a moderate CYP3A inducer), concurrent use was predicted to decrease ripretinib Cmax by 24% and decrease AUC by 56%.(1) In the presence of a strong CYP3A inducer, a doubled ripretinib dose (twice daily rather than once daily), is predicted to result in a 40% reduction in combined AUC of ripretinib and active metabolite DP-5439, compared to the usual recommended once daily dose with no inducer present.(2) In an interaction study of itraconazole (a strong CYP3A4 inhibitor) and ripretinib, concurrent use increased ripretinib Cmax by 36% and AUC by 99%. Concurrent use increased the AUC of DP-5439 by 99% with no change in Cmax.(1) Strong CYP3A4 inducers linked to this monograph are: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine and St John's Wort.(4,5)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Myelosuppressives; Immunomodulators/Sodium Iodide I 131

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Sodium iodide I 131 can cause depression of the hematopoetic system. Myelosuppressives and immunomodulators also suppress the immune system.(1)

CLINICAL EFFECTS: Concurrent use of sodium iodide I 131 with agents that cause bone marrow depression, including myelosuppressives or immunomodulators, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of sodium iodide I 131 states that concurrent use with bone marrow depressants may enhance the depression of the hematopoetic system caused by large doses of sodium iodide I 131.(1) Sodium iodide I 131 causes a dose-dependent bone marrow suppression, including neutropenia or thrombocytopenia, in the 3 to 5 weeks following administration. Patients may be at increased risk of infections or bleeding during this time. Monitor complete blood counts within one month of therapy. If results indicate leukopenia or thrombocytopenia, dosimetry should be used to determine a safe sodium iodide I 131 activity.(1)

DISCUSSION: Hematologic disorders including death have been reported with sodium iodide I 131. The most common hematologic disorders reported include anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia.(1)

Ripretinib/Moderate Cyp3a4 Inducers

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Moderate inducers of CYP3A4 may induce the metabolism of ripretinib via this pathway.(1) Ripretinib and the active metabolite DP-5439 contribute to anticancer activity. CYP3A4 is the primary metabolism pathway for both ripretinib and the active metabolite DP-5439.(1)

CLINICAL EFFECTS: Concurrent or recent use of moderate CYP3A4 inducers may alter the clinical effectiveness of ripretinib.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Avoid the concurrent use of ripretinib with moderate CYP3A4 inducers.(1-3) When possible, select alternative agents in place of the moderate CYP3A4 inducer. If the moderate CYP3A4 inducer cannot be avoided, increase the dose of ripretinib from 150 mg once daily to 150 mg twice daily during concurrent therapy. Monitor patients receiving concurrent therapy for reduced efficacy.(1-3) If the moderate CYP3A4 inducer is discontinued, reduce the dose of ripretinib back to 150 mg once daily 14 days after discontinuation of the moderate CYP3A4 inducer.(1-3) If a dose of ripretinib is missed (in patients taking twice daily dosing): -If less than 4 hours have passed since missed dose, patient should take the dose as soon as possible and then take the next dose at the regularly scheduled time. -If more than 4 hours have passed since missed dose, patient should skip the missed dose and then take the next dose at the regularly scheduled time.(1-3)

DISCUSSION: The primary metabolism pathway for ripretinib and DP-5439 is via CYP3A4.(1) In an interaction study of rifampin (a strong CYP3A inducer) and ripretinib, concurrent use decreased ripretinib concentration maximum (Cmax) by 18% and area-under-curve (AUC) by 61%, as well as decreased the active metabolite DP-5439 AUC by 57% and increased Cmax by 37%.(1) In a pharmacokinetic model of efavirenz (a moderate CYP3A inducer), concurrent use was predicted to decrease ripretinib Cmax by 24% and decrease AUC by 56%.(1) In the presence of a moderate CYP3A inducer, a doubled ripretinib dose (twice daily rather than once daily), is predicted to result in a 17% reduction in combined AUC of ripretinib and active metabolite DP-5439, compared to the usual recommended once daily dose with no inducer present.(2) In an interaction study of itraconazole (a strong CYP3A4 inhibitor) and ripretinib, concurrent use increased ripretinib Cmax by 36% and AUC by 99%. Concurrent use increased the AUC of DP-5439 by 99% with no change in Cmax.(1) Moderate CYP3A4 inducers linked to this monograph are: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(4,5)

There are no moderate interactions for this drug.

*None.

• Invasive surgical procedure
• Lactation
• Left ventricular failure

• Hypertension
• Impaired wound healing
• Palmar-plantar erythrodysesthesia
• Pregnancy

• Pre-malignant skin lesion

Adverse effects reported in at least 20% of patients receiving ripretinib for the treatment of GI stromal tumor (GIST) include alopecia, fatigue, nausea, abdominal pain, constipation, myalgia, diarrhea, decreased appetite, palmar-plantar erythrodysesthesia syndrome, and vomiting. The most common grade 3 or 4 laboratory abnormalities (>=4%) were increased lipase and decreased phosphate.

More Frequent

• Elevated serum lipase
• Hypophosphatemia

Less Frequent

• Anemia
• Heart failure
• Hyperbilirubinemia
• Hypertension
• Hypocalcemia
• Impaired wound healing
• Keratoacanthoma
• Malignant melanoma
• Neutropenic disorder
• Squamous cell carcinoma of skin

Rare or Very Rare

• Acute myocardial infarction

More Frequent

• Acute abdominal pain
• Alopecia
• Anorexia
• Constipation
• Diarrhea
• Fatigue
• Myalgia
• Nausea
• Palmar-plantar erythrodysesthesia
• Vomiting

Less Frequent

• Arthralgia
• Dyspnea
• Headache disorder
• Muscle spasm
• Peripheral sensory neuropathy
• Pruritus of skin
• Stomatitis
• Weight loss

Rare or Very Rare

• Acneiform eruption
• Skin photosensitivity
• Skin rash

No enhanced messaging available.

Safety and efficacy of ripretinib have not been established in pediatric patients. In animal toxicology studies, ripretinib has been associated with changes in growing teeth (missing or discolored teeth accompanied by dose-dependent incisor degeneration) and bones (decreased trabeculae of the femur, increased osteoblastic surface).

Ripretinib may cause fetal harm if administered to pregnant females based on its mechanism of action.

It is not known whether ripretinib or its metabolites are distributed into human milk. The effects of the drug on breast-fed infants or on the production of milk are unknown.

Because of the potential for serious adverse reactions to ripretinib in breast-fed infants, females should be advised not to breast-feed while receiving the drug and for at least 1 week after the last dose.

The manufacturer makes no specific dosage recommendations for geriatric patients.

In the INVICTUS study, 24% of patients receiving ripretinib were 65 years of age or older, while 9% were 75 years of age or older. The manufacturer states that insufficient data are available to determine whether geriatric patients respond differently than younger adults.

Population pharmacokinetic analysis suggests that age (range: 19-87 years) does not have a clinically important effect on the pharmacokinetics of ripretinib.