DRUG INTERACTIONS- summary

 Strong CYP3A Inhibitors:                                                                                                   Monitor more frequently for adverse reactions. 

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

U.S. FDA APPROVED  DRUGS DURING 2020

Sr.No-  19

ADVERSE REACTIONS

 The most common adverse reactions (=20%) were alopecia, fatigue, nausea, abdominal pain, constipation, myalgia, diarrhea, decreased appetite, palmarplantar erythrodysesthesia, and vomiting.

The most common Grade 3 or 4 laboratory abnormalities (=4%) were increased lipase and decreased phosphate.

 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. 

Embryo-Fetal Toxicity:                                                                                                          Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. 

PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Palmar-Plantar Erythrodysesthesia Syndrome-                                                          Advise patients to contact their healthcare provider immediately if they experience severe skin changes 

New Primary Cutaneous Malignancies-                                                                       Advise patients to contact their healthcare provider immediately for change in or development of new skin lesions 

Hypertension-                                                                                                                     Advise patients that hypertension may develop during treatment with QINLOCK and that blood pressure should be monitored regularly during treatment.

Cardiac Dysfunction-                                                                                                       Advise patients that cardiac failure may develop during treatment with QINLOCK 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.

Risk of Impaired Wound Healing-                                                                                       Advise patients that QINLOCK may impair wound healing. Advise patients to inform their healthcare provider of any planned surgical procedure.

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 

Use in Specific Populations-                                                                                                 Advise females of reproductive potential to use effective contraception during treatment with QINLOCK 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 QINLOCK and for at least 1 week after the final dose 

Lactation -                                                                                                                           Advise females not to breastfeed during treatment with QINLOCK and for at least 1 week after the final dose 

Infertility-                                                                                                                            Advise males of reproductive potential that QINLOCK may impair fertility.

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

Dosage and Administration-                                                                                                    Instruct patients to take QINLOCK 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 QINLOCK 

Storage Instructions-                                                                                                                    Store QINLOCK in the original container at room temperature between 20ºC to 25ºC (68ºF to 77ºF).

Manufactured for and marketed by: Deciphera Pharmaceuticals, LLC 200 Smith Street, Waltham, MA 02451

CLINICAL PHARMACOLOGY-.

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.

2. Pharmacodynamics Exposure-                                                                          Response Relationships-                                                                                       Ripretinib exposure-response relationships and the time course of pharmacodynamics have not been fully characterized.

Cardiac Electrophysiology-                                                                                          No large mean increase in QTc interval (i.e. >20 ms) was detected following treatment with QINLOCK at the recommended dose of 150 mg taken orally once daily.

3. Pharmacokinetics-                                                                                                   The pharmacokinetics of ripretinib and its equally active metabolite (DP-5439) were evaluated following single doses in healthy subjects and multiple doses in patients with advanced malignancies; the results were ascertained.

Effect of Food-                                                                                                               No clinically significant differences in the Cmax and AUC0-24h were observed between administration of QINLOCK with a high-fat mealc and under fasted conditions.

Distribution-                                                                                                              Plasma protein binding (in vitro) Human serum albumin 99.8% 99.7% a-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%                                                 .   -Estimated based on cycle 1, day                                                                               -. -    -After a single oral dose of 150 mg-.A high fat meal consisted of approximately 150, 250, and 500-600 calories from protein, carbohydrate, and fat, respectively CV=coefficient of variation; Cmax=maximum plasma concentration;

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) or moderate to severe hepatic impairment (total bilirubin >1.5 × ULN, AST any) on the pharmacokinetics of ripretinib have not been studied.

Drug Interaction Studies -                                                                                      Strong CYP3A Inhibitors:                                                                                    Coadministration of QINLOCK with itraconazole (a strong CYP3A inhibitor and also a P-gp inhibitor) increased ripretinib Cmax by 36% and AUC0-INF by 99% and also increased DP-5439 AUC0-INF by 99% with no change in its Cmax.

Strong CYP3A Inducers:                                                                                              The effect of coadministration of QINLOCK with a strong CYP3A inducer has not been studied. Ripretinib and DP-5439 are metabolized by CYP3A.

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 inhibitors of CYP2C8. Ripretinib and DP-5439 are not inducers of CYP1A2, CYP2B6, or CYP3A4.

Transporter Systems: Ripretinib is an inhibitor of P-gp (P-glycoprotein) and BCRP (Breast Cancer Resistance Protein). DP-5439 is a substrate for P-gp and BCRP. DP-5439 is an inhibitor of BCRP and MATE1 (Multidrug And Toxin Extrusion Protein 1).

 USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary-                                                                                         Based on findings from animal studies and its mechanism of action 

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.

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.

2. 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 QINLOCK and for at least 1 week after the final dose.

3. Females and Males of Reproductive Potential -                                                        QINLOCK can cause fetal harm when administered to a pregnant woman 

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

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

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

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

4. Pediatric Use-                                                                                                              The safety and effectiveness of QINLOCK in pediatric patients have not been established.

Animal Toxicity Data-                                                                                                      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). .

5. Geriatric Use-                                                                                                                   Of the 85 patients in INVICTUS who received QINLOCK 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 QINLOCK did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently from younger patients.

6. 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 AST any).

A recommended dosage of QINLOCK has not been established for patients with moderate or severe hepatic impairment