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Ripretinib

Class: Antineoplastic Agents
Chemical Name: 1-[4-bromo-5-[1-ethyl-7-(methylamino)-2-oxo-1,6-naphthyridin-3-yl]-2-fluorophenyl]-3-phenylurea
Molecular Formula: C24H21BrFN5O2
CAS Number: 1442472-39-0
Brands: Qinlock

Medically reviewed by Drugs.com. Last updated on Jun 1, 2020.

Introduction

Ripretinib is an antineoplastic agent.

Uses for Ripretinib

Ripretinib has the following uses:

Ripretinib is a kinase inhibitor indicated for the treatment of adult patients with advanced gastrointestinal stromal tumor (GIST) who have received prior treatment with 3 or more kinase inhibitors, including imatinib.1

Ripretinib Dosage and Administration

General

Ripretinib is available in the following dosage form(s) and strength(s):

Tablets: 50 mg.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration
  • Recommended dosage: 150 mg orally once daily, with or without food, until disease progression or unacceptable toxicity occurs.1

  • Swallow tablets whole.1

  • Consult manufacturer’s labeling for recommended dosage modifications for adverse reactions.1

Cautions for Ripretinib

Contraindications

None.1

Warnings/Precautions

Palmar-plantar Erythrodysesthesia Syndrome

In the principal efficacy study (INVICTUS), Grade 1–2 palmar-plantar erythrodysesthesia syndrome (PPES) occurred in 21% of the 85 patients who received ripretinib. PPES led to dose discontinuation in 1.2% of patients, dose interruption in 2.4% of patients, and dose reduction in 1.2% of patients. 1

Based on severity, withhold ripretinib and then resume at same or reduced dose. 1

New Primary Cutaneous Malignancies

In the INVICTUS study, cutaneous squamous cell carcinoma (cuSCC) occurred in 4.7% of the 85 patients who received ripretinib, with a median time to event of 4.6 months (range: 3.8 to 6 months). In the pooled safety population, cuSCC and keratoacanthoma occurred in 7% and 1.9% of 351 patients who received ripretinib, respectively. 1

Melanoma occurred in 2.4% of the 85 of patients who received ripretinib in INVICTUS. In the pooled safety population, melanoma occurred in 0.9% of 351 patients who received ripretinib. 1

Perform dermatologic evaluations when initiating ripretinib and routinely during treatment. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Continue ripretinib at the same dose. 1

Hypertension

In the INVICTUS study, Grade 1–3 hypertension occurred in 14% of the 85 patients who received ripretinib, including Grade 3 hypertension in 7%. 1

Do not initiate ripretinib in patients with uncontrolled hypertension. Adequately control blood pressure prior to initiating ripretinib. Monitor blood pressure as clinically indicated during treatment with ripretinib, and initiate or adjust antihypertensive therapy as appropriate. Based on severity, withhold ripretinib and then resume at same or reduced dose or permanently discontinue. 1

Cardiac Dysfunction

In the INVICTUS study, cardiac failure occurred in 1.2% of the 85 patients who received ripretinib. In the pooled safety population, cardiac dysfunction (including cardiac failure, acute left ventricular failure, diastolic dysfunction, and ventricular hypertrophy) occurred in 1.7% of 351 patients who received ripretinib, including Grade 3 adverse reactions in 1.1%. 1

In INVICTUS, Grade 3 decreased ejection fraction occurred in 2.6% of the 77 patients who received ripretinib and who had a baseline and at least one post-baseline echocardiogram. In the pooled safety population, Grade 3 decreased ejection fraction occurred in 3.4% of the 263 patients who received ripretinib and who had a baseline and at least one post-baseline echocardiogram. 1

In INVICTUS, cardiac dysfunction led to dose discontinuation in 1.2% of the 85 patients who received ripretinib. The safety of ripretinib has not been assessed in patients with a baseline ejection fraction below 50%. 1

Assess ejection fraction by echocardiogram or MUGA scan prior to initiating ripretinib and during treatment, as clinically indicated. Permanently discontinue ripretinib for Grade 3 or 4 left ventricular systolic dysfunction. 1

Risk of Impaired Wound Healing

Impaired wound healing complications can occur in patients who receive drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. Therefore, ripretinib has the potential to adversely affect wound healing. 1

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. The safety of resumption of ripretinib after resolution of wound healing complications has not been established. 1

Embryo-fetal Toxicity

Based on findings from animal studies and its mechanism of action, ripretinib can cause fetal harm when administered to a pregnant woman. Oral administration of ripretinib to pregnant rats and rabbits during the period of organogenesis resulted in malformations primarily associated with the cardiovascular and skeletal systems, anatomic variations, decreased fetal body weight, and increased post-implantation loss at exposures approximately one half of the recommended dose of 150 mg once daily based on area under the curve (AUC). 1

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ripretinib and for at least 1 week after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with ripretinib and for at least 1 week after the final dose. 1

Specific Populations

Pregnancy

Risk Summary: Based on findings from animal studies and its mechanism of action, ripretinib can cause fetal harm when administered to a pregnant woman. There are no available data on the use of ripretinib in pregnant women to inform a drug-associated risk. Administration of ripretinib to pregnant rats and rabbits during the period of organogenesis resulted in malformations primarily associated with the cardiovascular and skeletal systems, anatomic variations, reduced fetal body weight, and increased post-implantation loss at maternal exposures that were approximately equal to the human exposure at the recommended dose of 150 mg. Advise pregnant women of the potential risk to a fetus. 1

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. 1

Animal Data: In an embryo-fetal development study investigating daily doses of ripretinib administered during the period of organogenesis in rats, ripretinib resulted in malformations primarily associated with the cardiovascular and skeletal systems, including interrupted or retroesophageal aortic arch and retroesophageal subclavian artery, fusion of the exoccipital bone to the first cervical vertebra, branched and fused ribs, anomalies of the cervical, thoracic, caudal, and sacral vertebrae, absent forepaw phalanges, and absent metacarpals at a dose of 20 mg/kg/day (approximately one half of the human exposure at the recommended dose of 150 mg). An increased incidence of anatomic variations were also observed at 20 mg/kg/day. Variations included malpositioned carotid and subclavian artery origins, malpositioned subclavian artery, absent or elongated innominate artery, misshapen and nodulated ribs, bipartite, incompletely ossified, or unossified vertebral centra, small or misshapen vertebral arches, and reductions in ossified forelimb and hindlimb phalanges, hindlimb metatarsals, and caudal vertebrae. 1

In a preliminary embryo-fetal development study investigating the administration of ripretinib in rabbits during the period of organogenesis, ripretinib resulted in total loss of pregnancy at doses of 150 mg/kg (approximately 3.5 times the human exposure at the recommended dose of 150 mg). At a dose of 40 mg/kg (approximately 2.1 times the human exposure at the recommended dose of 150 mg), toxicities included increased post-implantation loss and decreased fetal body weights. 1

Lactation

Risk Summary: There are no data regarding the presence of ripretinib or its metabolites in either human milk or its effects on a breastfed child or on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with ripretinib and for at least 1 week after the final dose. 1

Females and Males of Reproductive Potential

Ripretinib can cause fetal harm when administered to a pregnant woman. 1

Verify pregnancy status of females of reproductive potential prior to the initiation of ripretinib. 1

Advise females of reproductive potential to use effective contraception during treatment and for at least 1 week after the final dose. 1

Advise males with female partners of reproductive potential to use effective contraception during treatment and for at least 1 week after the final dose. 1

Based on findings from animal studies, ripretinib may impair fertility in males of reproductive potential. 1

Pediatric Use

The safety and effectiveness of ripretinib in pediatric patients have not been established. 1

In 13-week repeat-dose studies in rats there were dose-dependent findings of increased osteoblastic surface and decreased trabeculae of the femur at doses ≥30 mg/kg/day (approximately one half of the human exposure at the recommended dose of 150 mg). There were additional findings of missing or discolored teeth that were accompanied by dose-dependent incisor degeneration at doses ≥30 mg/kg/day. 1

Geriatric Use

Of the 85 patients in the INVICTUS study who received ripretinib 150 mg orally once daily, 24% were between 65 to 74 years of age and 9% were 75 years of age or older. Clinical studies of ripretinib did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently from younger patients. 1

Hepatic Impairment

No dose adjustment is recommended in patients with mild hepatic impairment (total bilirubin ≤ULN and AST >ULN or total bilirubin 1 to 1.5 × ULN and any AST). A recommended dosage of ripretinib has not been established for patients with moderate or severe hepatic impairment. 1

Common Adverse Effects

The most common adverse reactions (≥20%) were alopecia, fatigue, nausea, abdominal pain, constipation, myalgia, diarrhea, decreased appetite, palmar-plantar erythrodysesthesia, and vomiting. The most common Grade 3 or 4 laboratory abnormalities (≥4%) were increased lipase and decreased phosphate.1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

  • Strong CYP3A Inhibitors: Monitor more frequently for adverse reactions.1

  • Strong CYP3A Inducers: Avoid concomitant use of strong CYP3A inducers.1

Actions

Mechanism of Action

Ripretinib is a tyrosine kinase inhibitor that inhibits KIT proto-oncogene receptor tyrosine kinase (KIT) and platelet derived growth factor receptor A (PDGFRA) kinase, including wild type, primary, and secondary mutations. Ripretinib also inhibits other kinases in vitro, such as PDGFRB, TIE2, VEGFR2, and BRAF. 1

Advice to Patients

Advise the patient to read the FDA-approved patient labeling. 1

Palmar-Plantar Erythrodysesthesia Syndrome

Advise patients to contact their healthcare provider immediately if they experience severe skin changes. 1

New Primary Cutaneous Malignancies

Advise patients to contact their healthcare provider immediately for change in or development of new skin lesions. 1

Hypertension

Advise patients that hypertension may develop during treatment with ripretinib and that blood pressure should be monitored regularly during treatment. 1

Cardiac Dysfunction

Advise patients that cardiac failure may develop during treatment with ripretinib and that signs or symptoms of cardiac failure should be regularly monitored during treatment. Advise patients to contact their healthcare provider immediately for signs or symptoms of cardiac dysfunction. 1

Risk of Impaired Wound Healing

Advise patients that ripretinib may impair wound healing. Advise patients to inform their healthcare provider of any planned surgical procedure. 1

Embryo-Fetal Toxicity

Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy. 1

Advise females of reproductive potential to use effective contraception during treatment with ripretinib and for at least 1 week after the final dose. 1

Advise males with female partners of reproductive potential to use effective contraception during treatment with ripretinib and for at least 1 week after the final dose.1

Lactation

Advise females not to breastfeed during treatment with ripretinib and for at least 1 week after the final dose. 1

Infertility

Advise males of reproductive potential that ripretinib may impair fertility. 1

Drug Interactions

Advise patients to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products. 1

Dosage and Administration

Instruct patients to take ripretinib at the same time each day (once daily) with or without food. Advise patients to swallow tablets whole. Inform patients about what to do in the event they miss a dose or vomit after taking a dose of ripretinib. 1

Storage Instructions

Store ripretinib in the original container at room temperature between 20ºC to 25ºC (68ºF to 77ºF). 1

Additional Information

AHFSfirstRelease. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

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

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablet

50 mg

Qinlock

Decipera Pharmaceuticals LLC

AHFS Drug Information. © Copyright 2020, Selected Revisions June 1, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Decipera Pharmaceuticals, LLC. QINLOCK (Ripretinib) ORAL prescribing information. 2020 May. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9f18e462-03dd-4296-a02a-a0577e3ee78d