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Ripretinib

Medically reviewed by Drugs.com. Last updated on May 17, 2020.

Pronunciation

(rip RE ti nib)

Index Terms

  • DCC-2618
  • DCC2618
  • KIT/PDGFR Inhibitor DCC-2618
  • Qinlock

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Qinlock: 50 mg

Brand Names: U.S.

  • Qinlock

Pharmacologic Category

  • Antineoplastic Agent, KIT Inhibitor
  • Antineoplastic Agent, PDGFR-alpha Blocker
  • Antineoplastic Agent, Tyrosine Kinase Inhibitor

Pharmacology

Ripretinib is a switch control tyrosine kinase inhibitor that inhibits KIT proto-oncogene receptor tyrosine kinase (KIT) and platelet derived growth factor receptor A (PDGFRA) kinase signaling (George 2020). It binds to both wild type and mutant forms (including primary and secondary mutations) of KIT and PDGRA, preventing the switch from inactive to active conformations of these kinases. Ripretinib also inhibits other kinases, including PDGFRB, TIE2, VEGFR2, and BRAF.

Distribution

Vd: Ripretinib: 307 L; DP-5439 (active metabolite): 507 L.

Metabolism

Ripretinib: Primarily hepatic via CYP3A4 (major) and CYP2C8 and CYP2D6 (both minor); DP-5439 (active metabolite) via CYP3A4 (major) and CYP2C8, CYP2E1, and CYP2D6 (all minor).

Excretion

Ripretinib: Feces (34%); urine (<1%); DP-5439: Feces (6%); Urine: (<1%).

Clearance: Ripretinib: 15.3 L/hour; DP-5439: 17.5 L/hour.

Time to Peak

Ripretinib: 4 hours; DP-5439: 15.6 hours.

Half-Life Elimination

Ripretinib: 14.8 hours; DP-5439: 17.8 hours.

Protein Binding

Ripretinib: >99% to albumin and α-1 acid glycoprotein; DP-5439: >99% to albumin and α-1 acid glycoprotein.

Use: Labeled Indications

Gastrointestinal stromal tumor, advanced: Treatment of advanced gastrointestinal stromal tumor (GIST) in adults who have previously received treatment with ≥3 kinase inhibitors, including imatinib.

Contraindications

There are no contraindications listed in the manufacturer's labeling.

Dosing: Adult

Note: Withhold ripretinib for at least 1 week prior to elective surgery; do not administer for at least 2 weeks following major surgery and until adequate wound healing has occurred.

Gastrointestinal stromal tumor, advanced: Oral: 150 mg once daily until disease progression or unacceptable toxicity (Blay 2020).

Missed dose: Administer a missed dose if <8 hours have passed since the missed scheduled dose. If vomiting occurs, do not administer an additional dose; resume at the next scheduled dose.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

Recommended dose reduction level for adverse reactions: Reduce ripretinib dose to 100 mg once daily. Permanently discontinue ripretinib if unable to tolerate 100 mg once daily.

Recommended Ripretinib Dose Reductions for Adverse Reactions

Adverse reaction

Severitya

Ripretinib dosage modifications

aSeverity grades per Nation Cancer Institute Common Toxicity Criteria for Adverse Events version 4.03.

Arthralgia or myalgia

Grade 2

Withhold ripretinib until ≤ grade 1 or baseline. If recovered within 7 days, resume ripretinib at same dose; otherwise resume ripretinib at a reduced dose. Consider reescalating the ripretinib dose if arthralgia or myalgia maintained at ≤ grade 1 or baseline for at least 28 days. If arthralgia or myalgia recur, withhold ripretinib until resolved to ≤ grade 1 or baseline, and then resume ripretinib at a reduced dose (regardless of time to improvement).

If arthralgia or myalgia recur, withhold ripretinib until resolved to ≤ grade 1 or baseline, and then resume ripretinib at a reduced dose (regardless of time to improvement).

Grade 3

Withhold ripretinib for at least 7 days or until ≤ grade 1 or baseline (maximum 28 days), then resume ripretinib at a reduced dose. Consider reescalating the ripretinib dose if arthralgia or myalgia maintained at ≤ grade 1 or baseline for at least 28 days.

Hypertension

Initiate or adjust antihypertensive therapy during ripretinib treatment as appropriate.

Grade 3

If symptomatic, withhold ripretinib until symptoms have resolved and BP is controlled. If BP is controlled to ≤ grade 1 or baseline, resume ripretinib at the same dose; otherwise, resume ripretinib at a reduced dose.

If grade 3 hypertension recurs, withhold ripretinib until symptoms have resolved and BP is controlled, and then resume ripretinib at a reduced dose.

Grade 4

Permanently discontinue ripretinib.

Left ventricular systolic dysfunction

Grade 3 or 4

Permanently discontinue ripretinib.

Palmar-plantar erythrodysesthesia syndrome (PPES)

Grade 2

Withhold ripretinib until ≤ grade 1 or baseline. If recovered within 7 days, resume ripretinib at the same dose; otherwise, resume ripretinib at a reduced dose. Consider reescalating the ripretinib dose if PPES maintained at ≤ grade 1 or baseline for at least 28 days. If PPES recurs, withhold ripretinib until resolved to ≤ grade 1 or baseline, and then resume ripretinib at a reduced dose (regardless of time to improvement).

Grade 3

Withhold ripretinib for at least 7 days or until ≤ grade 1 or baseline (maximum 28 days), then resume ripretinib at a reduced dose. Consider reescalating the ripretinib dose if PPES maintained at ≤ grade 1 or baseline for at least 28 days.

Other adverse reactions

Grade 3 or 4

Withhold ripretinib until ≤ grade 1 or baseline (maximum 28 days), and then resume ripretinib at a reduced dose; otherwise permanently discontinue.

If no recurrence of the adverse reaction for at least 28 days, consider reescalating the ripretinib dose. If grade 3 or 4 adverse reaction recurs, permanently discontinue ripretinib.

Administration

Oral: Administer at approximately the same time each day, with or without food. Swallow tablets whole.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursion permitted between 15°C to 30°C (59°F to 86°F). Dispense in original container only. Store in the original container with desiccant to protect from moisture and light. Replace cap securely each time after opening. Do not discard desiccant.

Drug Interactions

Abametapir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Aprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Ripretinib. Avoid combination

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Ripretinib. Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Duvelisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fosnetupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Larotrectinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Solriamfetol: May enhance the hypertensive effect of Hypertension-Associated Agents. Monitor therapy

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Adverse Reactions

>10%:

Cardiovascular: Hypertension (14% [placebo: 5%]), peripheral edema (17%)

Dermatologic: Alopecia (52% [placebo: 5%]), palmar-plantar erythrodysesthesia (21% [placebo: 0%]), pruritus (11%), xeroderma (13%)

Endocrine & metabolic: Decreased serum calcium (23%), decreased serum phosphate (26%), decreased serum sodium (17%), increased serum triglycerides (26%), weight loss (19%)

Gastrointestinal: Abdominal pain (36%), constipation (34%), decreased appetite (27%), diarrhea (28%), increased serum amylase (13%), increased serum lipase (32%), nausea (39%), stomatitis (11%), vomiting (21%)

Hematologic & oncologic: Increased INR (21%; grades 3/4: 4%), prolonged partial thromboplastin time (35%)

Hepatic: Increased serum alanine aminotransferase (12%), increased serum bilirubin (22%)

Nervous system: Fatigue (42%), headache (19%)

Neuromuscular & skeletal: Arthralgia (18%), increased creatine phosphokinase in blood specimen (21%), muscle spasm (15%), myalgia (32%)

Respiratory: Dyspnea (13%)

1% to 10%:

Cardiovascular: Cardiac disorder (2%; including left ventricular failure, ventricular hypertrophy), cardiac failure (grade 3: 1% [placebo: 0%]) Blay 2020, ischemic heart disease (1%; including acute coronary syndrome, acute myocardial infarction), reduced ejection fraction (grade 3: 3%)

Hematologic & oncologic: Anemia (4%), keratoacanthoma (2%), malignant melanoma (≤2%), neutropenia (10%), squamous cell carcinoma of skin (5% to 7%)

Frequency not defined:

Nervous system: Agitation, hyperesthesia

Neuromuscular & skeletal: Arthritis

Warnings/Precautions

Concerns related to adverse effects:

• Cardiotoxicity: Cardiac failure occurred in a small percentage of patients in the clinical trial. In a pooled safety population, cardiac dysfunction (including cardiac failure, acute left ventricular failure, diastolic dysfunction, and ventricular hypertrophy) also occurred in a small percentage of patients, including grade 3 cardiac adverse events. Cases of grade 3 decreased ejection fraction were observed among patients who received ripretinib and who had a baseline and at least 1 postbaseline echocardiogram. Cardiac dysfunction rarely led to ripretinib discontinuation. Assess ejection fraction by echocardiogram or multigated acquisition (MUGA) scan prior to ripretinib initiation and during treatment as clinically indicated. Permanently discontinue ripretinib for grade 3 or 4 left ventricular systolic dysfunction. The safety of ripretinib has not been assessed in patients with a baseline ejection fraction <50%.

• Dermatologic toxicity: Grades 1 and 2 palmar-plantar erythrodysesthesia syndrome (PPES) has occurred with ripretinib. Based on the severity, PPES may require treatment interruption and/or dose reduction. Case reports of discontinuation due to PPES have been reported.

• GI toxicity: Nausea, vomiting, abdominal pain, constipation, and diarrhea have occurred; most instances were generally mild.

• Hypertension: Hypertension has been reported with ripretinib, including grade 3 events. BP should be adequately controlled prior to treatment initiation; do not initiate ripretinib in patients with uncontrolled hypertension. Monitor BP during ripretinib treatment as clinically indicated and initiate or adjust antihypertensive therapy as appropriate. Based on the severity, hypertension may require ripretinib treatment interruption, dose reduction, and/or permanent discontinuation.

• Malignancy: In a clinical trial with ripretinib, cutaneous squamous cell carcinoma (cuSCC) occurred in a small number of patients. The median time to occurrence was 4.6 months (range: 3.8 to 6 months). In a pooled safety population, cuSCC and keratoacanthoma occurred in small percentages of patients. Cases of melanoma have also been reported with ripretinib, both in the clinical trial and in the pooled safety population. Perform dermatologic evaluations when initiating ripretinib and routinely during ripretinib treatment. Suspicious skin lesions should be managed with excision and dermatopathologic evaluation (while continuing ripretinib at the same dose).

• Musculoskeletal toxicity: Arthralgia and/or myalgia have been reported; may require ripretinib treatment interruption and/or dose reduction.

• Wound healing impairment: Vascular endothelial growth factor (VEGF) receptor inhibitors are associated with impaired wound healing; therefore, ripretinib may have the potential to adversely affect wound healing. Withhold ripretinib for at least 1 week prior to elective surgery; do not administer for at least 2 weeks following major surgery and until adequate wound healing has occurred. The safety of resuming ripretinib treatment after resolution of wound healing complications has not been established.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Monitoring Parameters

Assess ejection fraction by echocardiogram or multigated acquisition (MUGA) scan prior to ripretinib initiation and during treatment as clinically indicated. Monitor BP (prior to and during treatment). Evaluate pregnancy status prior to use in females of reproductive potential. Perform dermatologic evaluations when initiating ripretinib and routinely during ripretinib treatment. Monitor for signs/symptoms of palmar-plantar erythrodysesthesia syndrome, wound healing impairment, and arthralgia/myalgia. Monitor adherence.

Reproductive Considerations

Evaluate pregnancy status prior to use in females of reproductive potential.

Females of reproductive potential should use effective contraception during therapy and for at least 1 week after the last ripretinib dose. Males with female partners of reproductive potential should use effective contraception during therapy and for at least 1 week after the last dose of ripretinib.

Pregnancy Considerations

Based on the mechanism of action and data from animal reproduction studies, in utero exposure to ripretinib may cause fetal harm.

Patient Education

What is this drug used for?

• It is used to treat cancer of the GI (gastrointestinal) tract.

Frequently reported side effects of this drug

• Hair thinning

• Hair loss

• Constipation

• Diarrhea

• Nausea

• Vomiting

• Lack of appetite

• Mouth irritation

• Mouth sores

• Loss of strength and energy

• Muscle pain

• Joint pain

• Muscle spasm

• Dry skin

• Itching

• Weight loss

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting

• Heart problems like cough or shortness of breath that is new or worse, swelling of the ankles or legs, abnormal heartbeat, weight gain of more than five pounds in 24 hours, dizziness, or passing out

• Severe headache

• Dizziness

• Passing out

• Vision changes

• Redness or irritation on palms of hands or soles of feet

• Bruising

• Bleeding

• Infection

• Skin growth

• Skin lump

• Skin changes

• Mole changes

• Wound healing impairment

• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Further information

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