Ripretinib (Monograph)

Brand name: Qinlock
Drug class: Antineoplastic Agents
- Kinase Inhibitors
- Receptor Tyrosine Kinase Inhibitors
- Tyrosine Kinase Inhibitors
Chemical name: N-{4-Bromo-5-[1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl]-2-fluorophenyl{-N′-phenylurea
Molecular formula: C₂₄H₂₁BrFN₅O₂
CAS number: 1442472-39-0

Medically reviewed by Drugs.com on Feb 28, 2022. Written by ASHP.

Introduction

Antineoplastic agent; an inhibitor of multiple receptor tyrosine kinases, including platelet-derived growth factor receptor alpha (PDGFR-α) and c-Kit.

Uses for Ripretinib

Gastrointestinal Stromal Tumor (GIST)

Ripretinib is used for the treatment of advanced gastrointestinal stromal tumor (GIST) in adults who previously received therapy with at least 3 tyrosine kinase inhibitors, including imatinib; designated an orphan drug by FDA for this use.

Ripretinib Dosage and Administration

General

Pretreatment Screening

• LVEF (e.g., echocardiogram, MUGA scan).

• Blood pressure must be adequately controlled prior to initiation of therapy.

• Dermatologic evaluation.

• Verify pregnancy status in females of reproductive potential.

Patient Monitoring

• LVEF (e.g., echocardiogram, MUGA scan) during therapy, and as clinically indicated.

• Blood pressure, as clinically indicated.

• Perform dermatologic evaluation routinely during therapy.

Other General Considerations

• Do not initiate in patients with uncontrolled hypertension.

• Withhold drug ≥1 week prior to elective surgery. Do not resume until ≥2 weeks following major surgery and after the surgical incision has adequately healed.

Administration

Oral Administration

Administer orally once daily without regard to meals.

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.

Dosage

Adults

GIST

Oral

150 mg once daily. Continue therapy until disease progression or unacceptable toxicity occurs.

Dosage Modification for Toxicity

Oral

If dosage modification is necessary, reduce dosage to 100 mg once daily; however, if 100 mg once daily is not tolerated, permanently discontinue ripretinib.

Palmar-plantar Erythrodysesthesia Syndrome

Oral

If grade 2 palmar-plantar erythrodysesthesia syndrome occurs, withhold ripretinib until resolution to ≤grade 1 or to baseline. If resolution occurs within 7 days, resume therapy at the same dosage (150 mg once daily). If resolution occurs in >7 days, resume therapy at a reduced dosage of 100 mg once daily; if resolution is maintained for ≥28 days on a reduced dosage, may re-escalate dosage to 150 mg once daily.

If grade 2 palmar-plantar erythrodysesthesia syndrome recurs on a dosage of 150 mg once daily, withhold ripretinib until resolution to ≤grade 1 or to baseline, and then resume at a reduced dosage (100 mg once daily) regardless of time to improvement.

If grade 3 palmar-plantar erythrodysesthesia syndrome occurs, withhold ripretinib for ≥7 days or until resolution to ≤grade 1 or to baseline (maximum of 28 days). If resolution occurs, may resume at a reduced dosage (100 mg once daily). If resolution of palmar-plantar erythrodysesthesia syndrome is maintained for ≥28 days on a reduced dosage, may re-escalate dosage to 150 mg once daily.

Hypertension

Oral

If symptomatic grade 3 hypertension occurs, withhold ripretinib until symptoms resolve and BP is controlled. If hypertension resolves to ≤grade 1 or to baseline, resume therapy at the same dosage (150 mg once daily). If hypertension does not resolve to ≤grade 1 or to baseline, resume therapy at a reduced dosage of 100 mg once daily.

If grade 3 hypertension recurs, withhold ripretinib; when symptoms resolve and BP is controlled, resume therapy at a reduced dosage of 100 mg once daily.

If grade 4 hypertension occurs, permanently discontinue ripretinib.

Cardiac Dysfunction

Oral

If grade 3 or 4 left ventricular systolic dysfunction occurs, permanently discontinue ripretinib.

Arthralgia or Myalgia

Oral

If grade 2 arthralgia or myalgia occurs, withhold ripretinib until resolution to ≤grade 1 or to baseline. If recovery occurs within 7 days, resume therapy at the same dosage (150 mg once daily). If grade 2 arthralgia or myalgia does not resolve within 7 days, resume therapy at a reduced dosage (100 mg daily). If resolution is maintained for ≥28 days on a reduced dosage, may re-escalate dosage to 150 mg once daily. If grade 2 arthralgia or myalgia recurs on a dosage of 150 mg once daily, withhold ripretinib; when symptoms improve to ≤grade 1 or to baseline, resume therapy at a reduced dosage regardless of time to improvement.

If grade 3 arthralgia or myalgia occurs, withhold ripretinib for ≥7 days or until resolution to ≤grade 1 or to baseline (maximum of 28 days). If recovery occurs within 28 days, resume therapy at a reduced dosage of 100 mg once daily. If recovery is maintained for ≥28 days on a reduced dosage, may re-escalate dosage to 150 mg once daily.

Development of New Primary Cutaneous Malignancies

Oral

No dosage adjustment necessary.

Other Adverse Effects

Oral

If other grade 3 or 4 adverse reactions occur, withhold ripretinib until improvement to ≤grade 1 or to baseline. If resolution occurs, may resume therapy at a reduced dosage (100 mg once daily). If resolution does not occur within 28 days, permanently discontinue ripretinib. If recovery to ≤grade 1 or to baseline is maintained for ≥28 days on a reduced dosage of 100 mg once daily, may re-escalate dosage to 150 mg once daily. If grade 3 or 4 adverse reactions recur, permanently discontinue ripretinib.

Concomitant Use with Moderate CYP3A Inducers

Oral

If concomitant use of a moderate CYP3A inducer cannot be avoided, increase dosage of ripretinib from 150 mg once daily to 150 mg twice daily and monitor for clinical response and tolerability of the drug. If concomitant use of a moderate CYP3A inducer is discontinued, return ripretinib dosage to 150 mg once daily.

Special Populations

Hepatic Impairment

Mild (total bilirubin concentration not exceeding the ULN with AST concentration exceeding the ULN or total bilirubin concentration exceeding the ULN, but ≤1.5 times the ULN) hepatic impairment: No dosage adjustment required.

Moderate or severe (total bilirubin concentration >1.5 times the ULN with any AST concentration) hepatic impairment: No specific dosage recommendations at this time.

Renal Impairment

No specific dosage recommendations at this time.

Geriatric Patients

No specific dosage recommendations at this time.

Cautions for Ripretinib

Contraindications

• Manufacturer states none known.

Warnings/Precautions

Palmar-plantar Erythrodysesthesia Syndrome

Palmar-plantar erythrodysesthesia syndrome (PPES) reported in 21% of 85 ripretinib-treated patients.

Temporary interruption followed by dosage adjustment may be necessary depending on severity of palmar-plantar erythrodysesthesia syndrome.

Development of New Primary Cutaneous Malignancies.

In the INVICTUS study, cutaneous squamous cell carcinoma or melanoma were reported in 4.7 or 2.4% of 85 ripretinib-treated patients, respectively. The median time to development of cutaneous squamous cell carcinoma was 4.6 months (range: 3.8–6 months).

Perform dermatologic evaluation prior to initiating therapy and routinely during therapy. Initiate appropriate therapy and excise suspicious cutaneous lesions for pathologic evaluation; no dosage adjustment necessary.

Hypertension

Hypertension reported in 14% of 85 patients with GIST receiving ripretinib; grade 3 or 4 hypertension reported in 7% of ripretinib-treated patients.

Assess BP prior to initiating therapy; BP must be adequately controlled prior to initiation of therapy. Do not initiate ripretinib therapy in patients with uncontrolled hypertension. During therapy, monitor BP as clinically indicated and initiate or adjust antihypertensive therapy as appropriate.

Temporary interruption followed by dosage adjustment or permanent discontinuance of therapy may be necessary depending on the severity of the hypertension. (See Hypertension under Dosage and Administration.)

Cardiac Dysfunction

Cardiac failure was reported in 1.2% of patients receiving ripretinib; grade 3 decreased ejection fraction reported in 2.6% of 77 patients. Permanent discontinuance of therapy was necessary in 1.2% of 85 patients experiencing cardiac dysfunction. Safety of ripretinib not evaluated in patients with a baseline left ventricular ejection fraction (LVEF) <50%.

Assess LVEF (e.g., echocardiogram, MUGA scan) prior to initiating therapy, during therapy, and as clinically indicated. If grade 3 or 4 left ventricular systolic dysfunction occurs, permanently discontinue therapy.

Surgery and Wound Healing Complications

Effect of ripretinib on wound healing not specifically studied; however, VEGFR inhibitors may impair wound healing.

Withhold ripretinib therapy ≥1 week prior to elective surgery. Do not resume therapy until ≥2 weeks after major surgery and after the surgical incision has adequately healed. Safety of resuming therapy postoperatively after resolution of wound healing complications not established.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; embryofetal toxicity (i.e., decreased fetal body weight, postimplantation loss) and teratogenic effects (i.e., cardiovascular and skeletal malformations) observed in animals.

Avoid pregnancy during therapy. Perform pregnancy test prior to initiation of ripretinib in females of reproductive potential. Females of reproductive potential should use effective methods of contraception during therapy and for ≥1 week after drug discontinuance. If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.

Males with female partners of reproductive potential should use effective methods of contraception during therapy and for ≥1 week after drug discontinuance.

Impairment of Fertility

Animal studies suggest ripretinib may impair male fertility.

Specific Populations

Pregnancy

May cause fetal harm.

Avoid pregnancy during therapy. Perform pregnancy test prior to initiation of ripretinib in females of reproductive potential.

Lactation

Not known whether ripretinib is distributed into human milk. Effects on breast-fed infants and milk production also unknown. Discontinue breast-feeding during therapy and for ≥1 week after the last dose.

Pediatric Use

Safety and efficacy not established.

Changes in growing teeth and bones reported in animals.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults.

Hepatic Impairment

Pharmacokinetics not substantially altered by mild hepatic impairment; dosage adjustment not necessary in such patients.

Not studied in patients with moderate or severe hepatic impairment.

Renal Impairment

Pharmacokinetics not substantially altered by mild or moderate renal impairment.

Not studied in patients with severe renal impairment.

Common Adverse Effects

Adverse effects reported in ≥20% of patients receiving ripretinib for the treatment of GIST: Alopecia, fatigue, nausea, abdominal pain, constipation, myalgia, diarrhea, decreased appetite, palmar-plantar erythrodysesthesia syndrome, vomiting, elevated APTT, elevated lipase concentration, hypophosphatemia, elevated triglyceride concentration, hypocalcemia, elevated bilirubin concentration, elevated INR, elevated creatine kinase (CK, creatine phosphokinase, CPK) concentration.

Interactions for Ripretinib

Ripretinib is metabolized principally by CYP3A4 and, to a lesser extent, by CYP2C8 and CYP2D6 to active 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 inhibits 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.

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP3A inhibitors: Possible increased exposure to, and increased toxicity of, ripretinib. If used concomitantly, monitor frequently for signs of ripretinib toxicity.

Potent CYP3A inducers: Possible decreased systemic exposure to, and decreased efficacy of, ripretinib. Avoid concomitant use.

Moderate CYP3A Inducer: Possible decreased systemic exposure to ripretinib and DP-5439, and reduced ripretinib efficacy. Avoid concomitant use. If concomitant use cannot be avoided, increase dosage of ripretinib from 150 mg once daily to 150 mg twice daily. Monitor for clinical response and tolerability of the drug. If concomitant use of a moderate CYP3A inducer is discontinued, return ripretinib dosage to 150 mg once daily.

Specific Drugs

Ripretinib Pharmacokinetics

Absorption

Bioavailability

AUC of ripretinib is dose proportional and peak plasma concentrations are less than dose proportional over the ripretinib dose range of 20–250 mg daily. AUC and peak plasma concentrations of DP-5439 are less than dose proportional over the ripretinib dose range of 50–250 mg daily.

Following oral administration of a single dose, peak plasma concentrations of ripretinib and DP-5439 attained in a median of 4 and 15.6 hours, respectively.

Steady-state concentrations of ripretinib and DP-5439 achieved within 14 days.

Food

No clinically significant differences in peak plasma concentrations and AUC observed between administration of ripretinib with a high-fat meal and under fasted conditions.

Special Populations

Mild hepatic impairment (total bilirubin concentration not exceeding the ULN with AST concentration exceeding ULN, or total bilirubin concentration exceeding ULN, but not >1.5 times the ULN, with any AST concentration) does not affect pharmacokinetics of ripretinib.

Moderate or severe hepatic impairment (total bilirubin concentrations >1.5 times ULN with any AST concentration): Pharmacokinetics not studied.

Mild or moderate renal impairment (Cl_cr 30 to <90 mL/minute) does not affect pharmacokinetics of ripretinib.

Severe renal impairment (Cl_cr 15–29 mL/minute): Pharmacokinetics not studied.

Age (range: 19–87 years), sex, race, and body weight (39–138 kg) do not affect pharmacokinetics of ripretinib and DP-5439.

Distribution

Extent

Not known whether ripretinib or its metabolites distribute into milk.

Plasma Protein Binding

Ripretinib and DP-5439: >99% (mainly albumin and α1-acid glycoprotein).

Elimination

Metabolism

Metabolized by CYP3A4, and to a lesser extent by CYP2C8 and CYP2D6, to its major active metabolite, DP-5439. DP-5439 metabolized by CYP3A4, and to a lesser extent by CYP isoenzymes 2C8, 2E1, and 2D6.

Elimination Route

Excreted in feces (34%), as unchanged drug and, to a lesser extent, as DP-5439 (6%); <0.1% of dose eliminated in urine.

Half-life

Ripretinib: 14.8 hours.

DP-5439: 17.8 hours.

Stability

Storage

Oral

Tablets

20–25°C (excursions permitted between 15–30°C).

Actions

• Type II tyrosine switch control inhibitor with broad activity against c-KIT and PDGFR-α, including wild-type, and primary and secondary mutations associated with resistance to other tyrosine kinase inhibitors.

• Oncogenic kinase mutations, such as activating mutations in the c-KIT receptor tyrosine kinase gene (present in approximately 80% of patients with GIST), result in dysregulated switch control and constitutive activation of c-KIT and PDGFR-α, leading to abnormal cell growth and survival.

• In vitro, also inhibits PDGF-β, tyrosine kinase with immunoglobulin and epidermal growth factor homology (TIE-2), vascular endothelial growth factor (VEGF)-2, and b-Raf serine-threonine kinase (BRAF).

Advice to Patients

• Importance of reading the manufacturer’s patient information prior to beginning ripretinib therapy and rereading it each time the prescription is refilled.

• Importance of advising patients to take ripretinib as directed by their clinician at approximately the same time each day. Importance of swallowing the tablets whole.

• If a dose of ripretinib is missed by 8 hours or less, importance of administering the missed dose on the same day as soon as it is remembered and taking the next dose at the regularly scheduled time on the following day. Advise patients not to take 2 doses on the same day to make up for a missed dose. If a dose is vomited, importance of administering the next dose at the regularly scheduled time; an additional dose should not be administered to replace the vomited dose.

• Risk of palmar-plantar erythrodysesthesia syndrome or rash. Importance of promptly informing clinician of skin changes (e.g., redness, pain, blisters, bleeding, swelling) on the hands or feet or severe rash.

• Risk of new primary cutaneous malignancies. Importance of contacting a clinician promptly if dermatologic changes (e.g., new wart, skin sore or reddish bump that bleeds or does not heal, or mole that changes in size or color) occur.

• Risk of hypertension developing or worsening during therapy. Importance of regular monitoring of blood pressure during treatment.

• Risk of heart failure. Importance of immediately reporting swelling of the abdomen, legs or ankles; fatigue; shortness of breath; or protruding neck veins.

• Risk of wound healing complications. Importance of informing clinician of any scheduled surgery or wounds that do not heal.

• Risk of fetal harm. Necessity of advising females of reproductive potential and males who are partners of such females that they must use an effective method of contraception while receiving ripretinib and for at least 1 week after discontinuance of therapy. Importance of patients informing their clinicians if they or their partners become pregnant. If pregnancy occurs, apprise patient of potential hazard to the fetus.

• Importance of advising females to avoid breast-feeding while receiving ripretinib therapy and for 1 week after the final dose.

• Risk of impaired male fertility.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., hypertension, cardiovascular disease).

• Importance of informing patients of other important precautionary information.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Ripretinib can only be obtained through a limited network of specialty pharmacies and distributors. Contact manufacturer for specific ordering and availability information.

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