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ripretinib
Ripretinib is a tyrosine kinase inhibitor. It inhibits KIT proto-oncogene receptor tyrosine kinase (KIT) and Platelet-Derived Growth Factor Receptor A (PDGFRA) kinase activity, including wild-type and multiple primary and secondary mutations. In vitro, ripretinib also inhibits PDGFRB, TIE2, VEGFR2, and BRAF.
Ripretinib has a dual mechanism of action. It binds to both the switch pocket and the activation loop, and locks the kinase in the inactive state, inhibiting downstream signaling and cell proliferation.
| Effects with food |
Although a high-fat, high-calorie meal increased AUC by 30% and Cmax by 22%, these changes were not considered clinically relevant. |
| T max |
2 hours (median at steady state) |
| Time to reach steady state |
15 days |
| PPB |
99% (albumin and α-1 acid glycoprotein) |
Ripretinib is primarily metabolized by CYP3A4/5 via N-dealkylation and oxidation pathways.
| Active metabolites |
Yes (DP-5439) |
| Feces |
34% (ripretinib); 6% (DP-5439) |
| Urine |
0.02% (ripretinib); 0.1% (DP-5439) |
| Half-life |
14.8 hours (ripretinib); 17.8 hours (DP-5439) |
- Gastrointestinal stromal tumor (GIST)
Refer to the product monograph for a full list and details of approved indications.
Emetogenic Potential:
The following adverse events were reported in ≥ 10% of patients with advanced GIST who were treated with ripretinib in a Phase 3 study. It also included severe or life-threatening adverse events from other sources.
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Cardiac ischemia (1%) (may be severe) | E | |||
| Cardiotoxicity (1%) | E | ||||
| Ejection fraction decreased (3%) (severe) | E | ||||
| Hypertension (14%) (7% severe) | E | ||||
| Dermatological | Alopecia (52%) | E D | |||
| Dry skin (13%) (including pruritus) | E | ||||
| Hand-foot syndrome (21%) | E | ||||
| Photosensitivity (<10%) | E | ||||
| Gastrointestinal | Abdominal pain (37%) | E | |||
| Anorexia, weight loss (27%) | E | ||||
| Constipation (34%) | E | ||||
| Diarrhea (28%) | E | ||||
| Mucositis (11%) | E | ||||
| Nausea, vomiting (39%) (4% severe) | E | ||||
| General | Delayed wound healing (observed with other VEGF inhibitors) | E | |||
| Edema - limbs (17%) | E | ||||
| Fatigue (42%) | E | ||||
| Hepatobiliary | ↑ Bilirubin (17%) | E | |||
| ↑ Lipase (11%) | E | ||||
| Hypersensitivity | Hypersensitivity (rare) | I E | |||
| Metabolic / Endocrine | ↓ PO4 (11%) | E | |||
| Musculoskeletal | Musculoskeletal pain (32%) | E | |||
| Neoplastic | Secondary malignancy (5%) (SCC of the skin, melanoma) | D L | |||
| Nervous System | Headache (19%) | E | |||
| Respiratory | Dyspnea (13%) | E | |||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
The most common side effects for ripretinib include alopecia, fatigue, nausea, vomiting, abdominal pain, constipation, musculoskeletal pain, diarrhea, anorexia, weight loss, hand-foot syndrome and headache.
Squamous cell carcinoma (SCC) of the skin was reported with a median onset of ~5 months. No dose reduction or interruption is required for actinic keratosis or new primary cutaneous malignancies.
Refer to protocol by which the patient is being treated.
Screen for hepatitis B virus in all cancer patients starting systemic treatment. Refer to the hepatitis B virus screening and management guideline.
Blood pressure should be adequately controlled prior to initiation of ripretinib. Hold ripretinib for at least 3 days prior to and after minor surgery and at least 5 days prior to and after major surgery. The decision to resume after surgery should be based on clinical judgment of adequate wound healing.
Other supportive care:
- Due to risk of photosensitivity, patients should avoid or minimize exposure to strong sunlight or other sources of UV radiation until at least 1 week after discontinuation of treatment. They should use a sunscreen and wear protective clothing to cover the skin when exposed to strong sunlight.
| Dose Levels | Ripretinib Dose (mg daily) |
| 0 | 150 |
| -1 | 100 |
| -2 | Discontinue permanently. |
| Toxicity | Severity | Action |
| Hand-foot syndrome | Grade 2 |
Hold* for at least 7 days. If resolves within 7 days, resume at same dose level. If resolves after 7 days, resume at 1 dose level ↓.
If recurs, hold*. Resume at 100 mg regardless of time to improvement. |
| Grade 3 |
Hold* for at least 7 days (maximum 28 days). Resume at 1 dose level ↓. Consider re-escalation if maintained at Grade 1 or baseline for at least 28 days. |
|
| Hypertension | Grade 3 |
Medically manage to achieve < Grade 1. If symptomatic, hold until symptoms resolve.
If recurs despite dose modification and medical management, discontinue. |
| Grade 4 Life-threatening consequences (e.g., malignant hypertension, transient or permanent neurologic deficit, hypertensive crisis) |
Discontinue. | |
| Arthralgia, myalgia | Grade 2 |
Hold* for at least 7 days. If resolves within 7 days, resume at same dose level. If resolves after 7 days, resume at 1 dose level ↓.
If recurs, hold*. Resume at reduced dose level (i.e. 100 mg) regardless of time to improvement. |
| Grade 3 |
Hold* for at least 7 days (maximum 28 days). Resume at 1 dose level ↓; otherwise, discontinue. Consider re-escalation if maintained at Grade 1 or baseline for at least 28 days. |
|
| Left ventricular systolic dysfunction | Grade 3 or 4 | Discontinue |
| Isolated Bilirubin Increased | Grade 2 |
Hold* (maximum 28 days). Restart with 1 dose level ↓. |
| Grade 3 or 4 | See "Other toxicities" below. | |
| Actinic keratosis | Any |
No dose modification required. Patients with suspicious skin lesions should be referred for evaluation immediately. |
| New primary cutaneous malignancies | ||
| Other toxicities | Grade 3 or 4 |
Hold* (maximum 28 days), then resume at 1 dose level ↓; otherwise, discontinue. Consider re-escalation if maintained at Grade 1 or baseline for at least 28 days. Discontinue at recurrence. |
*Do not resume until hand-foot syndrome, musculoskeletal pain, increased bilirubin, or other toxicities resolve to Grade 1 or baseline.
No dose adjustment is recommended in patients with hepatic impairment (Child-Pugh A, B or C).
| Creatinine Clearance (mL/min) | Ripretinib Dose |
| > 30 | No dose adjustment required |
| < 30 | Not studied |
No dose adjustment required in patients of ≥ 65 years of age. Although data are limited, no differences in safety or efficacy were observed between patients ≥ 65 years of age and patients < 65 years.
Sex does not appear to have a clinically relevant effect on the pharmacokinetics of ripretinib.
Ethnicity does not have a clinically meaningful effect on the pharmacokinetics of ripretinib.
The safety and efficacy of ripretinib in children < 18 years have not been established. Alterations of teeth and bones/cartilage were documented in animal studies and may indicate a potential risk for children < 18 years.
-
Ripretinib may be taken with or without food at about the same time each day.
-
Tablets should be swallowed whole and not chewed, split, or crushed.
-
Grapefruit, starfruit, Seville oranges, their juices or products should be avoided during ripretinib treatment
-
For patients taking 150 mg once daily (standard dose): if a dose is missed, patient may take within 8 hours of missed dose. If more than 8 hours, the dose should be skipped and taken at the next planned time. Extra doses should not be taken to make up for missed dose.
-
For patients taking 150 mg twice daily (with strong or moderate CYP3A4 inducers): if a dose is missed, patient may take within 4 hours of missed dose. If more than 4 hours, the dose should be skipped and taken at the next planned time. Extra doses should not be taken to make up for missed dose.
-
If patient vomits after taking a dose, an additional dose should not be taken. The next dose should be continued as scheduled.
-
Store at room temperature (15°C to 25°C) in the original container.
- Patients who are hypersensitive to this drug or any of its components
- Use caution and monitor more frequently in patients who have experienced hypersensitivity with prior use of other tyrosine kinase inhibitors.
- Patients with a baseline LVEF < 50%, CrCl < 50 mL/min, creatinine > 1.5 x ULN, or bilirubin > 1.5 x ULN and/or AST > 3 x ULN (> 5 x ULN with hepatic metastases) were excluded from clinical trials. Consider the benefits vs risks of using ripretinib in these patients.
Other Drug Properties:
-
Carcinogenicity:
No information available
-
Phototoxicity:
Documented in humans
-
Mutagenicity:
Not observed in in vitro or in vivo assays
-
Embryotoxicity:
Documented in animals
-
Fetotoxicity:
Documented in animals
-
Pregnancy:
Ripretinib is not recommended for use in pregnancy.
-
Adequate contraception should be used by patients who can become pregnant and their partners starting 2 weeks before treatment, during treatment, and for at least 1 complete uterine cycle after the last dose.
-
Adequate contraception should be used by patients who produce sperm and their partners starting 2 weeks before treatment, during treatment, and for at least 1 complete uterine cycle (of the partner) after the last dose.
-
It is not known if ripretinib can affect hormonal contraception. If a hormonal contraception method must be used, a barrier method of contraception (e.g. condoms) must be used together with the hormonal contraception.
-
-
Breastfeeding:
Breastfeeding is not recommended during treatment, and for at least 2 weeks after the last dose.
-
Fertility effects:
Documented in studies with male animals. Discuss fertility preservation with patients prior to starting treatment.
CYP3A4/5 is the major metabolizer of ripretinib. Coadministration of strong CYP3A inhibitors or inducers affected the exposure to ripretinib and DP-5439.
Ripretinib and DP-5439 are likely to inhibit CYP2C8. Ripretinib is not an inducer of CYP1A2, CYP2B6, and CYP3A4.
Ripretinib is an inhibitor of P-gp and BCRP. DP-5439 is an inhibitor of BCRP and MATE1. In addition, DP-5439 is a substrate for P-gp and BCRP.
No clinically significant differences in exposure to ripretinib were observed when coadministered with pantoprazole.
Effects of ripretinib on hormonal contraceptives have not been studied. A barrier method of contraception (e.g. condoms) should be added if hormonal contraceptives are used.
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| Strong CYP3A inhibitors (e.g. ketoconazole, itraconazole) | ↑ ripretinib exposure (↑ AUC by 99% with itraconazole) | ↓ metabolism of ripretinib | Caution; monitor ripretinib toxicities closely. |
| Grapefruit juice | ↑ ripretinib exposure | ↓ metabolism of ripretinib | Caution; monitor ripretinib toxicities closely. |
| Strong and moderate CYP3A4 inducers (e.g. phenytoin, rifampin, dexamethasone, carbamazepine, phenobarbital, St. John’s Wort, etc) | ↓ ripretinib exposure (↓ AUC by 61% with rifampin) | ↑ metabolism of ripretinib | Avoid concomitant use with strong or moderate CYP3A inducers. If must use a strong or moderate inducer, increase ripretinib dose to 150 mg twice daily. If inducer is discontinued, decrease ripretinib dose to previous dose 14 days after discontinuation of inducer. |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
Refer to the hepatitis B virus screening and management guideline for monitoring during and after treatment.
| Monitor Type | Monitor Frequency |
|---|---|
CBC |
Baseline, monthly, and as clinically indicated |
Liver function tests |
Baseline, monthly, and as clinically indicated |
Renal function tests |
Baseline, monthly, and as clinically indicated |
Blood pressure |
Baseline, monthly, and as clinically indicated |
LVEF (ECG or MUGA scan) |
Baseline and as clinically indicated |
Skin assessment (for new primary cutaneous malignancies) |
Baseline and as clinically indicated |
Clinical toxicity assessment for hypersensitivity, delayed wound healing (if applicable), musculoskeletal, gastrointestinal, cardiovascular, and skin effects |
At each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
Exceptional Access Program (EAP Website )
- ripretinib - For adult patients with advanced gastrointestinal stromal tumours (GIST) who have progression on or intolerance to imatinib, sunitinib and regorafenib
Blay J-Y, Serrano C, Heinrich MC, et al. Ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol 2020 Jul;21(7):923-34.
CADTH reimbursement recommendation: ripretinib (advanced gastrointestinal stromal tumour). May 2022.
NCCN Guidelines. Antiemesis. May 24, 2023.
Prescribing Information: QINLOCK® (ripretinib) tablets, for oral use. Deciphera Pharmaceuticals, LLC. December 2022.
Product Monograph: Qinlock (ripretinib). Deciphera Pharmaceuticals, LLC. July 9, 2024.
December 2025 New drug monograph
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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