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About This Medication
11 DESCRIPTION Ripretinib is a kinase inhibitor. The chemical name of ripretinib is 1-(4-bromo-5-[1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl]-2-fluorophenyl)-3-phenylurea. The molecular formula is C 24 H 21 BrFN 5 O 2 and the molecular weight is 510.36 g/mol. The chemical structure of ripretinib is shown below: Ripretinib is a white to off-white crystalline solid. Ripretinib is a lipophilic, weak base, and practically insoluble in aqueous media. QINLOCK is available as a white to off-white, oval tablets for oral use containing 50 mg of ripretinib. The tablet is debossed with “DC1” on one side. Each tablet contains the following inactive ingredients: crospovidone, hypromellose acetate succinate, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and silicon dioxide. Figure
Bahan Aktif
| Bahan |
Kekuatan |
| Ripretinib |
- |
Indikasi & Penggunaan
1 INDICATIONS AND USAGE QINLOCK is 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. QINLOCK 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 )
Cara kerja
12.1 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.
Dosis & Cara Pemberian
2 DOSAGE AND ADMINISTRATION Recommended Dosage : 150 mg orally once daily with or without food. ( 2.1 ) 2.1 Recommended Dosage The recommended dosage of QINLOCK is 150 mg orally once daily with or without food until disease progression or unacceptable toxicity. Instruct patients to swallow tablets whole. Advise patients to take QINLOCK at the same time each day. Advise patients to take a missed dose if less than 8 hours have passed since the missed scheduled dose. Advise patients not to take an additional dose if vomiting occurs after taking QINLOCK and to continue with their next scheduled dose. 2.2 Dosage Modifications for Adverse Reactions The recommended dose reduction for adverse reactions is: QINLOCK 100 mg orally once daily. Permanently discontinue QINLOCK in patients who are unable to tolerate 100 mg orally once daily. The recommended dosage modifications of QINLOCK for adverse reactions are provided in Table 1 . Table 1: Recommended Dosage Modifications for QINLOCK for Adverse Reactions Adverse Reaction Severity a QINLOCK Dosage Modifications a Graded per National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 (NCI CTCAE v4.03). Palmar-Plantar Erythrodysesthesia Syndrome (PPES) [see Warnings and Precautions ( 5.1 )] Grade 2 Withhold QINLOCK until Grade ≤1 or baseline. If recovered within 7 days, resume QINLOCK at same dose; otherwise resume at reduced dose. Consider re-escalating QINLOCK if maintained at Grade ≤1 or baseline for at least 28 days. If PPES recurs, withhold QINLOCK until Grade ≤1 or baseline and then resume QINLOCK at a reduced dose regardless of time to improvement. Grade 3 Withhold QINLOCK for at least 7 days or until Grade ≤1 or baseline (maximum 28 days). Resume QINLOCK at a reduced dose. Consider re-escalating QINLOCK if maintained at Grade ≤1 or baseline for at least 28 days. Hypertension [see Warnings and Precautions ( 5.3 )] Grade 3 If symptomatic, withhold QINLOCK until symptoms have resolved and blood pressure is controlled. If blood pressure is controlled to Grade ≤1 or baseline, resume QINLOCK at the same dose; otherwise, resume QINLOCK at reduced dose. If Grade 3 hypertension recurs, withhold QINLOCK until symptoms have resolved and blood pressure is controlled. Resume QINLOCK at a reduced dose. Grade 4 Permanently discontinue QINLOCK. Left Ventricular Systolic Dysfunction [see Warnings and Precautions ( 5.4 )] Grade 3 or 4 Permanently discontinue QINLOCK. Arthralgia or Myalgia [see Adverse Reactions ( 6.1 )] Grade 2 Withhold QINLOCK until Grade ≤1 or baseline. If recovered within 7 days, resume QINLOCK at same dose; otherwise resume QINLOCK at reduced dose. Consider re-escalating QINLOCK if maintained at Grade ≤1 or baseline for at least 28 days. If arthralgia or myalgia recurs, withhold QINLOCK until Grade ≤1 or baseline and then resume QINLOCK at a reduced dose regardless of time to improvement. Grade 3 Withhold QINLOCK for at least 7 days or until Grade ≤1 or baseline (maximum of 28 days). Resume QINLOCK at a reduced dose. Consider re-escalating QINLOCK if maintained at Grade ≤1 or baseline for at least 28 days. Other Adverse Reactions [see Adverse Reactions ( 6.1 )] Grade 3 or 4 Withhold QINLOCK until Grade ≤1 or baseline (maximum 28 days), and then resume QINLOCK at a reduced dose; otherwise permanently discontinue. Consider re-escalating QINLOCK if no recurrence of the adverse reaction for at least 28 days. If Grade 3 or 4 recurs, permanently discontinue QINLOCK. 2.3 Dose Modifications for Moderate CYP3A Inducers Avoid concomitant use of moderate CYP3A inducers during QINLOCK treatment. If a moderate CYP3A inducer cannot be avoided, increase the QINLOCK dosing frequency from the recommended dose of 150 mg once daily to 150 mg twice daily during the co-administration period. Monitor for clinical response and tolerability. If the concomitant moderate CYP3A inducer is discontinued, resume QINLOCK dosage back to 150 mg once daily 14 days after the discontinuation of the moderate CYP3A inducer [see Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.3 )] . For patients concomitantly using a moderate CYP3A inducer with QINLOCK (taking QINLOCK twice daily) who missed a dose: If less than 4 hours have passed since the missed scheduled dose, advise the patient to take the missed dose as soon as possible and then take the next dose at the regularly scheduled time. If more than 4 hours have passed since the missed scheduled dose, advise the patient to skip the missed dose and then take the next dose at the regularly scheduled time. [see Drug Interactions ( 7.1 )] .
Side Effects Overview
6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed elsewhere in the labeling: Palmar-Plantar Erythrodysesthesia Syndrome [see Warnings and Precautions ( 5.1 )] New Primary Cutaneous Malignancies [see Warnings and Precautions ( 5.2 )] Hypertension [see Warnings and Precautions ( 5.3 )] Cardiac Dysfunction [see Warnings and Precautions ( 5.4 )] Photosensitivity [see Warnings and Precautions ( 5.6 )] 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. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Deciphera Pharmaceuticals, LLC, at 1-888-724-3274 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Unless otherwise specified, the pooled safety population described in the WARNINGS AND PRECAUTIONS reflect exposure to QINLOCK as a single agent in 351 patients with advanced solid tumors enrolled in either an open-label dose finding with cohort expansion trial or INVICTUS. Among the patients who received QINLOCK in these trials, 52% were exposed for 6 months or longer and 21% were exposed for greater than one year. Gastrointestinal Stromal Tumor Patients Who Received Prior Treatment with Imatinib, Sunitinib and Regorafenib The safety of QINLOCK was evaluated in INVICTUS [see Clinical Studies ( 14 )] . Patients received QINLOCK 150 mg taken orally once daily (n=85) or placebo (n=43). Among the patients who received QINLOCK, 46% were exposed for 6 months or longer and 3.5% were exposed for greater than one year. Serious adverse reactions occurred in 31% of patients who received QINLOCK. Serious adverse reactions that occurred in >2% of patients were abdominal pain (4.7%), anemia (3.5%), nausea (2.4%), and vomiting (2.4%). Permanent discontinuation due to an adverse reaction occurred in 8% of patients who received QINLOCK. Adverse reactions resulting in permanent discontinuation in ≥1% of patients included general physical health deterioration (2.4%), anemia (1.2%), cardiac failure (1.2%), PPES (1.2%), and vomiting (1.2%). Dosage interruptions due to an adverse reaction occurred in 24% of patients who received QINLOCK. Adverse reactions requiring dosage interruption in >2% of patients included nausea (3.5%), increased blood bilirubin (2.4%), and PPES (2.4%). Dose reductions due to an adverse reaction occurred in 7% of patients who received QINLOCK. Adverse reactions resulting in a dose reduction in ≥1.2% of patients were abdominal pain, agitation, alopecia, arthritis, dermatosis, gastrointestinal disorder, hyperesthesia, myalgia, PPES, and decreased weight. The most common adverse reactions (≥20%), were alopecia, fatigue, nausea, abdominal pain, constipation, myalgia, diarrhea, decreased appetite, PPES, and vomiting. The most common Grade 3 or 4 laboratory abnormalities (≥4%) were increased lipase and decreased phosphate. Table 2 summarizes the adverse reactions in INVICTUS. Table 2: Adverse Reactions (≥10%) in Patients with Gastrointestinal Stromal Tumor Who Received QINLOCK in INVICTUS Adverse Reaction QINLOCK (N=85) Placebo (N=43) Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 Skin and subcutaneous tissue Alopecia 52 0 4.7 0 Palmar-plantar erythrodysesthesia syndrome 21 0 0 0 Dry skin 13 0 7 0 Pruritus 11 0 4.7 0 General Fatigue 42 3.5 23 2.3 Peripheral edema 17 1.2 7 0 Asthenia 13 1.2 14 4.7 Gastrointestinal Nausea 39 3.5 12 0 Abdominal pain 36 7 30 4.7 Constipation 34 1.2 19 0 Diarrhea 28 1.2 14 2.3 Vomiting 21 3.5 7 0 Stomatitis 11 0 0 0 Musculoskeletal and connective tissue Myalgia 32 1.2 12 0 Arthralgia 18 0 4.7 0 Muscle spasms 15 0 4.7 0 Metabolism and nutrition Decreased appetite 27 1.2 21 2.3 Investigations Decreased weight 19 0 12 0 Nervous system Headache 19 0 4.7 0 Vascular Hypertension 14 7 4.7 0 Respiratory, thoracic and mediastinal Dyspnea 13 0 0 0 Table 3 summarizes the laboratory abnormalities in INVICTUS. Table 3: Select Laboratory Abnormalities (≥10%) Worsening from Baseline in Patients with Gastrointestinal Stromal Tumor Who Received QINLOCK with a Difference Between Arms of >5% Compared to Placebo in INVICTUS CPK=creatine phosphokinase; INR=international normalized ratio; AST=aspartate aminotransferase; ALT=alanine aminotransferase a. The denominator used to calculate the rate varied from 82 to 83 for QINLOCK and 34 to 40 for placebo based on the number of patients with a baseline value and at least one post-treatment value. b. Only includes Grade 3 laboratory abnormalities. Laboratory Abnormality QINLOCK a (N=85) Placebo a (N=43) Grades 1-4 Grades 3-4 b Grades 1-4 Grades 3-4 Hematology Increased activated partial thromboplastin time 35 0 9 0 Increased INR 21 3.8 15 0 Decreased neutrophil count 10 0 2.5 0 Chemistry Increased lipase 32 7 13 8 Decreased phosphate 26 4.9 2.5 0 Increased triglycerides 26 2.4 23 0 Decreased calcium 23 0 8 0 Increased blood bilirubin 22 0 5 2.5 Increased CPK 21 1.2 10 0 Decreased sodium 17 2.4 10 2.5 Increased creatinine 16 0 18 0 Increased serum amylase 13 1.2 5 0 Increased ALT 12 1.2 5 0 Other Adverse Reactions Clinically relevant adverse reactions that occurred in <10% of QINLOCK-treated patients in INVICTUS included peripheral sensory neuropathy, dermatitis acneiform, and rash. Clinically relevant adverse reactions that occurred in <10% of patients in the pooled safety population included cardiac ischemic events (including acute coronary syndrome and fatal cardiac arrest or myocardial infarction). Photosensitivity occurred in 0.6% [see Warnings and Precautions ( 5.6 )] .
Peringatan & Tindakan Pencegahan
5 WARNINGS AND PRECAUTIONS Palmar-Plantar Erythrodysesthesia Syndrome : Based on severity, withhold QINLOCK and resume at same or reduced dose. ( 2.2 , 5.1 ) New Primary Cutaneous Malignancies : Perform dermatologic evaluations when initiating QINLOCK and routinely during treatment. ( 5.2 ) Hypertension : Do not initiate QINLOCK in patients with uncontrolled hypertension and monitor blood pressure during treatment. Based on severity, withhold QINLOCK and then resume at same or reduced dose or permanently discontinue. ( 2.2 , 5.3 ) Cardiac Dysfunction : Assess ejection fraction by echocardiogram or MUGA scan prior to initiating QINLOCK and during treatment, as clinically indicated. Permanently discontinue QINLOCK for Grade 3 or 4 left ventricular systolic dysfunction. ( 2.2 , 5.4 ) Risk of Impaired Wound Healing : Withhold QINLOCK for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks after major surgery and until adequate wound healing. The safety of resumption of QINLOCK after resolution of wound healing complications has not been established. ( 5.5 ) Photosensitivity : May cause photosensitivity reactions. Advise patients to limit direct ultraviolet exposure. ( 5.6 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.7 , 8.1 , 8.3 ) 5.1 Palmar-Plantar Erythrodysesthesia Syndrome In INVICTUS, Grade 1-2 palmar-plantar erythrodysesthesia syndrome (PPES) occurred in 21% of the 85 patients who received QINLOCK [see Adverse Reactions ( 6.1 )]. 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. Based on severity, withhold QINLOCK and then resume at same or reduced dose [see Dosage and Administration ( 2.2 )] . 5.2 New Primary Cutaneous Malignancies In INVICTUS, cutaneous squamous cell carcinoma (cuSCC) occurred in 4.7% of the 85 patients who received QINLOCK, 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 patients, respectively. In INVICTUS, melanoma occurred in 2.4% of the 85 of patients who received QINLOCK. In the pooled safety population, melanoma occurred in 0.9% of patients. Perform dermatologic evaluations when initiating QINLOCK and routinely during treatment. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Continue QINLOCK at the same dose. 5.3 Hypertension In INVICTUS, Grade 1-3 hypertension occurred in 14% of the 85 patients who received QINLOCK, including Grade 3 hypertension in 7% [see Adverse Reactions ( 6.1 )] . Do not initiate QINLOCK in patients with uncontrolled hypertension. Adequately control blood pressure prior to initiating QINLOCK. Monitor blood pressure as clinically indicated during treatment with QINLOCK, and initiate or adjust antihypertensive therapy as appropriate. Based on severity, withhold QINLOCK and then resume at same or reduced dose or permanently discontinue [see Dosage and Administration ( 2.2 )] . 5.4 Cardiac Dysfunction In INVICTUS, cardiac failure occurred in 1.2% of the 85 patients who received QINLOCK. In the pooled safety population, cardiac dysfunction (including cardiac failure, acute left ventricular failure, diastolic dysfunction, and ventricular hypertrophy) occurred in 1.7% of patients, including Grade 3 adverse reactions in 1.1%. In INVICTUS, Grade 3 decreased ejection fraction occurred in 1.3% of the 77 patients who received QINLOCK and who had a baseline and at least one post-baseline echocardiogram. In the pooled safety population, Grade 3 decreased ejection fraction occurred in 1.9% of the 263 patients who received QINLOCK and who had a baseline and at least one post-baseline echocardiogram. In INVICTUS, cardiac dysfunction led to dose discontinuation in 1.2% of the 85 patients who received QINLOCK. The safety of QINLOCK has not been assessed in patients with a baseline ejection fraction below 50%. Assess ejection fraction by echocardiogram or MUGA scan prior to initiating QINLOCK and during treatment, as clinically indicated. Permanently discontinue QINLOCK for Grade 3 or 4 left ventricular systolic dysfunction [see Dosage and Administration ( 2.2 )] . 5.5 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, QINLOCK has the potential to adversely affect wound healing. Withhold QINLOCK 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 QINLOCK after resolution of wound healing complications has not been established. 5.6 Photosensitivity QINLOCK may cause photosensitivity reactions. In all patients treated with QINLOCK in clinical trials (n=621), photosensitivity reactions occurred in 0.6% of patients. Advise patients to limit direct ultraviolet exposure during treatment with QINLOCK and for at least one week after discontinuation of treatment. 5.7 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, QINLOCK 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). Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with QINLOCK and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with QINLOCK and for 1 week after the last dose [see Use in Specific Populations ( 8.1 , 8.3 ), Nonclinical Toxicology ( 13.1 )].
Kontraindikasi
4 CONTRAINDICATIONS None. None. ( 4 )
Farmakokinetik
12.3 Pharmacokinetics The pharmacokinetics of ripretinib and its equally active metabolite (DP-5439) were characterized in clinical studies. In patients with advanced malignancies, ripretinib AUC 0-24h increased proportionally over a dose range of 20-250 mg (0.13 to 1.67 times the recommended dose), but C max was less than dose proportional; DP-5439 C max and AUC 0-24h were less than dose proportional within the dose range of 50-250 mg (0.33 to 1.67 times the recommended dose). No clinically significant differences in the C max and AUC 0-24h were observed between administration of QINLOCK with a high-fat meal (150, 250, and 500-600 calories from protein, carbohydrate, and fat, respectively) and under fasted conditions. The pharmacokinetic parameters of ripretinib and DP-5439 are summarized in Table 5 . Table 5: Pharmacokinetic Parameters of Ripretinib and DP-5439 a. Estimated based on cycle 1, day 15 b. After a single oral dose of 150 mg CV=coefficient of variation; C max =maximum plasma concentration; AUC 0-12h =area under the plasma concentration-time curve from time zero to 12 hours; AUC 0-24h =area under the plasma concentration-time curve from time zero to 24 hours; T max =time to maximum concentration Parameter Ripretinib DP-5439 General Information Steady state exposure following QINLOCK 150 mg once daily [Mean (CV%)] C max (ng/mL) 761 (32) 804 (46) AUC 0-12h (ng•h/mL) 5678 (32) 7138 (44) Time to steady state [Days] 14 14 Accumulation ratio (AUC 0-12h ) [Mean (CV%)] a 1.7 (55) 5.29 (49) Absorption T max [Median in hours] b 4 15.6 Distribution Plasma protein binding (in vitro) Human serum albumin 99.8% 99.7% α-1 acid glycoprotein 99.4% >99.8% Steady state apparent volume of distribution, L [Mean (CV%)] b 307 (39) 507 (51) Elimination Apparent clearance, L/hr [Mean (CV%)] b 15.3 (45) 17.5 (63) Half-life, hours [Mean (CV%)] b 14.8 (30) 17.8 (23) Metabolism Metabolic pathways Major CYP3A4 CYP3A4 Minor CYP2C8 and CYP2D6 CYP2C8, CYP2E1 and CYP2D6 Excretion Excretion pathways Feces 34% 6% Urine 0.02% 0.1% Specific Populations No clinically significant differences in the pharmacokinetics of ripretinib were observed based on age (19 to 87 years), sex, race (White, Black, and Asian), body weight (39 to 138 kg), tumor (GIST or other solid tumors), prior gastrectomy, mild to moderate renal impairment (CLcr 30 to <90 mL/min estimated by Cockcroft-Gault), and mild hepatic impairment (total bilirubin ≤ULN and AST >ULN or total bilirubin 1 to 1.5 × ULN and AST any). The effects of severe renal impairment (CLcr 15 to 29 mL/min) on the pharmacokinetics of ripretinib have not been studied. Patients with Hepatic Impairment In subjects with mild hepatic impairment, there were no clinically significant changes in AUC 0-last and C max when compared to matched healthy subjects. In subjects with moderate hepatic impairment, ripretinib AUC 0-last increased 2-fold while C max was unchanged when compared to matched healthy subjects. The combined AUC 0-last of ripretinib and DP-5439 increased 1.5-fold. In subjects with severe hepatic impairment, ripretinib AUC 0-last increased 2.6-fold and C max decreased by 24% when compared to matched healthy subjects. The combined AUC 0-last of ripretinib and DP-5439 increased by 1.4-fold. The observed magnitude of increase in ripretinib and the combination of ripretinib and DP-5439 exposures in subjects with hepatic impairment is unlikely to be clinically relevant based on the known safety profile of ripretinib. Drug Interaction Studies Clinical Studies and Model-Informed Approaches CYP Enzymes: No clinically significant differences in the pharmacokinetics of repaglinide (a sensitive substrate for CYP2C8) were observed when used concomitantly with QINLOCK. Strong CYP3A Inhibitors: Coadministration of QINLOCK with itraconazole (a strong CYP3A inhibitor and also a P-gp inhibitor) increased ripretinib C max by 36% and AUC 0-inf by 99% and also increased DP-5439 AUC 0-inf by 99% with no change in its C max . Strong CYP3A Inducers: Coadministration of QINLOCK with rifampin (a strong CYP3A inducer) decreased ripretinib C max by 18% and AUC 0-inf by 61% and also decreased DP-5439 AUC 0-inf by 57% with increased C max by 37%. Moderate CYP3A Inducers: Coadministration of QINLOCK with efavirenz (a moderate CYP3A inducer) was predicted to decrease ripretinib C max by 24% and decrease AUC 0-inf by 56%. Proton Pump Inhibitors: No clinically significant differences in the plasma exposure to ripretinib and DP-5439 were observed when QINLOCK was coadministered with pantoprazole (a proton pump inhibitor). In Vitro Studies CYP Enzymes: Ripretinib and DP-5439 are not inducers of CYP1A2, CYP2B6, or CYP3A4. Transporter Systems: Ripretinib and DP-5439 are substrates for P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). Ripretinib is an inhibitor of P-gp and BCRP. DP-5439 is an inhibitor of BCRP and Multidrug And Toxin Extrusion Protein 1 (MATE1). UGT1A Substrates: Ripretinib is an inhibitor of UGT1A1, UGT1A3, UGT1A4, UGT1A7, and UGT1A8.