Qinlock (Ripretinib)

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.

Tablets: 50 mg, white to off-white, oval shaped, debossed with “DC1” on one side.

• Palmar-Plantar Erythrodysesthesia Syndrome
  : Based on severity, withhold QINLOCK and resume at same or reduced 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
  aGraded 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 ]	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 ]	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 ]	Grade 3 or 4	Permanently discontinue QINLOCK.
  Arthralgia or Myalgia [see Adverse Reactions ]	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 ]	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.
  ,
  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 ].

  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 ]

  .
  )
• New Primary Cutaneous Malignancies
  : Perform dermatologic evaluations when initiating QINLOCK and routinely during treatment. (
  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.
  )
• 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 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
  aGraded 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 ]	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 ]	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 ]	Grade 3 or 4	Permanently discontinue QINLOCK.
  Arthralgia or Myalgia [see Adverse Reactions ]	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 ]	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.
  ,
  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 ]

  .

  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 ]

  .
  )
• 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 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
  aGraded 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 ]	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 ]	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 ]	Grade 3 or 4	Permanently discontinue QINLOCK.
  Arthralgia or Myalgia [see Adverse Reactions ]	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 ]	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.
  ,
  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 ]

  .
  )
• 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 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.
  )
• Photosensitivity
  : May cause photosensitivity reactions. Advise patients to limit direct ultraviolet exposure. (
  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.
  )
• 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 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 , Nonclinical Toxicology ].
  , 
  8.1 Pregnancy

  Risk Summary

  Based on findings from animal studies and its mechanism of action

  [see Clinical Pharmacology ]

  , QINLOCK can cause fetal harm when administered to a pregnant woman. There are no available data on the use of QINLOCK 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 (see

  Data

  ). Advise pregnant women of the potential risk to a fetus.

  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.

  Data

  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.

  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.
  , 
  8.3 Females and Males of Reproductive Potential

  QINLOCK can cause fetal harm when administered to a pregnant woman

  [see Use in Specific Populations ]

  .

  Pregnancy Testing

  Verify pregnancy status of females of reproductive potential prior to the initiation of QINLOCK

  [see Use in Specific Populations ]

  .

  Contraception

  Females

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

  Males

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

  Infertility

  Based on findings from animal studies, QINLOCK may impair fertility in males of reproductive potential

  [see Nonclinical Toxicology ]

  .
  )