Version May 2024
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 (Ref).
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.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Note: CrCl calculated by Cockcroft-Gault equation.
CrCl ≥30 mL/minute: There are no dosage adjustments provided in the manufacturer’s labeling; however, CrCl between 30 to <90 mL/minute did not have any clinically meaningful effect on ripretinib pharmacokinetics.
CrCl <30 mL/minute: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).
Child-Pugh class A, B, or C: No dosage adjustment necessary.
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.
|
Adverse reaction |
Severity |
Ripretinib dosage modifications |
|---|---|---|
|
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 re-escalating 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 re-escalating 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 re-escalating 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 re-escalating the ripretinib dose if PPES maintained at ≤ grade 1 or baseline for at least 28 days. | |
|
Wound healing complications |
Any |
The safety of resuming ripretinib treatment after resolution of wound healing complications has not been established. |
|
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 re-escalating the ripretinib dose. If grade 3 or 4 adverse reaction recurs, permanently discontinue ripretinib. |
Refer to adult dosing.
Cardiac effects, including heart failure, acute coronary syndrome, acute myocardial infarction, left ventricular failure, reduced ejection fraction, ventricular hypertrophy, and hypertension have occurred. Only a small portion of cardiac effects led to discontinuation. The safety of ripretinib has not been assessed in patients with a baseline ejection fraction <50%.
Squamous cell carcinoma of the skin (cuSCC), malignant melanoma, and keratoacanthoma have occurred.
Onset: Delayed: cuSCC, median time to occurrence was 4.6 months (range: 3.8 to 6 months)
Dermatologic effects, including palmar-plantar erythrodysesthesia syndrome (PPES), skin photosensitivity, and alopecia have occurred. Only a small portion of these reactions resulted in discontinuation.
Onset: Onset and maximum severity of PPES and alopecia generally occurred simultaneously, suggesting no progressive worsening after first occurrence (Ref).
Risk factors:
Photosensitivity:
• Direct ultraviolet (UV) exposure
Wound healing may be adversely affected.
Mechanism: Vascular endothelial growth factor receptor inhibitors are associated with impaired wound healing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Cardiovascular: Hypertension (14%) (table 1), peripheral edema (17%)
|
Drug (Ripretinib) |
Placebo |
Number of Patients (Ripretinib) |
Number of Patients (Placebo) |
|---|---|---|---|
|
14% |
5% |
85 |
43 |
Dermatologic: Alopecia (52%) (table 2), palmar-plantar erythrodysesthesia (21%) (table 3), pruritus (11%), xeroderma (13%)
|
Drug (Ripretinib) |
Placebo |
Number of Patients (Ripretinib) |
Number of Patients (Placebo) |
|---|---|---|---|
|
14% |
5% |
85 |
43 |
|
Drug (Ripretinib) |
Placebo |
Number of Patients (Ripretinib) |
Number of Patients (Placebo) |
|---|---|---|---|
|
21% |
0% |
85 |
43 |
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), heart failure (grade 3: 1%) (table 4) (Blay 2020), ischemic heart disease (1%; including acute coronary syndrome, acute myocardial infarction), reduced ejection fraction (grade 3: 3%)
|
Drug (Ripretinib) |
Placebo |
Number of Patients (Ripretinib) |
Number of Patients (Placebo) |
Source |
|---|---|---|---|---|
|
Grade 3: 1% |
0% |
85 |
43 |
Blay 2020 |
Dermatologic: Malignant melanoma (≤2%), squamous cell carcinoma of skin (5% to 7%)
Hematologic & oncologic: Anemia (4%), keratoacanthoma (2%), neutropenia (10%)
<1%: Dermatologic: Skin photosensitivity
Frequency not defined:
Nervous system: Agitation, hyperesthesia
Neuromuscular & skeletal: Arthritis
Miscellaneous: Wound healing impairment
There are no contraindications listed in the manufacturer's US labeling.
Canadian labeling: Hypersensitivity to ripretinib or any component of the formulation.
Concerns related to adverse effects:
• Musculoskeletal toxicity: Arthralgia and/or myalgia have been reported; may require ripretinib treatment interruption and/or dose reduction.
• Photosensitivity: Patients should limit sun exposure during and for at least 1 week after ripretinib treatment. Advise patients to wear protective clothing and use broad-spectrum UVA/UVB sunscreen.
Special populations:
• Surgical patients: 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.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Qinlock: 50 mg
No
Tablets (Qinlock Oral)
50 mg (per each): $547.80
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Qinlock: 50 mg
Ripretinib is available through a specialty pharmacy network and specialty distributors; information may be found at QinlockHCP.com/resources or at 1.888.724.3274.
Oral: Administer at approximately the same time each day, with or without food. Swallow tablets whole.
This medication is not on the NIOSH (2016) list; however, it may meet the criteria for a hazardous drug. Ripretinib may cause teratogenicity and has a structural or toxicity profile similar to existing hazardous agents.
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.
Gastrointestinal stromal tumor, advanced: Treatment of advanced gastrointestinal stromal tumor (GIST) in adults who have previously received treatment with 3 or more kinase inhibitors, including imatinib.
Ripretinib may be confused with avapritinib, ceretinib, imatinib, regorafenib, rucaparib, ruxolitinib, sunitinib.
This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes that have a heightened risk of causing significant patient harm when used in error.
Substrate of BCRP/ABCG2, CYP2C8 (minor), CYP2D6 (minor), CYP2E1 (minor), CYP3A4 (major), P-glycoprotein/ABCB1 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Androgens: Hypertension-Associated Agents may enhance the hypertensive effect of Androgens. Risk C: Monitor therapy
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Ripretinib. Management: Avoid this combination if possible. If concomitant use is required, increase ripretinib to 150 mg twice daily. Decrease ripretinib to 150 mg once daily 14 days after stopping a moderate CYP3A4 inducer. Monitor patients for ripretinib response and toxicity Risk D: Consider therapy modification
CYP3A4 Inducers (Strong): May decrease the serum concentration of Ripretinib. Risk X: Avoid combination
CYP3A4 Inhibitors (Strong): May increase serum concentrations of the active metabolite(s) of Ripretinib. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ripretinib. Risk C: Monitor therapy
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Solriamfetol: May enhance the hypertensive effect of Hypertension-Associated Agents. Risk C: Monitor therapy
Evaluate pregnancy status prior to use in patients who could become pregnant.
Patients who could become pregnant should use effective contraception during therapy and for 1 week after the last ripretinib dose. Patients with partners who could become pregnant should use effective contraception during therapy and for 1 week after the last dose of ripretinib.
Based on the mechanism of action and data from animal reproduction studies, in utero exposure to ripretinib may cause fetal harm.
It is not known if ripretinib is present in breast milk.
Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer during therapy and for at least 1 week after the last ripretinib dose.
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 patients who could become pregnant. 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.
The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
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 (Blay 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.
Protein binding: Ripretinib: >99% to albumin and α-1 acid glycoprotein; DP-5439: >99% to albumin and α-1 acid glycoprotein.
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).
Half-life elimination: Ripretinib: 14.8 hours; DP-5439: 17.8 hours.
Time to peak: Ripretinib: 4 hours; DP-5439: 15.6 hours.
Excretion: Ripretinib: Feces (34%); urine (<1%); DP-5439: Feces (6%); Urine: (<1%).
Clearance: Ripretinib: 15.3 L/hour; DP-5439: 17.5 L/hour.
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