DRUG INTERACTIONS-(Summary)

 Strong or Moderate CYP3A Inhibitors: Avoid coadministration.

 Strong or Moderate CYP3A Inducers: Avoid coadministration.

 Gastric Acid Reducing Agents: Avoid coadministration. If coadministration cannot be avoided, stagger administration of TRUSELTIQ from H2­ antagonist or locally-acting antacid.

DRUG INTERACTIONS-(details)

Effects of Other Drugs on TRUSELTIQ Strong and Moderate CYP3A Inhibitors- Concomitant use of TRUSELTIQ with a strong or moderate CYP3A inhibitor may increase infigratinib plasma concentrations [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions.

Avoid concomitant use of TRUSELTIQ with strong or moderate CYP3A inhibitors.

Strong and Moderate CYP3A Inducers-                                                                    Concomitant use of TRUSELTIQ with a strong or moderate CYP3A inducer may decrease infigratinib plasma concentrations , which may reduce TRUSELTIQ anti-tumor activity.

Avoid concomitant use of TRUSELTIQ with strong or moderate CYP3A inducers.

Gastric Acid Reducing Agents-                                                                                          The coadministration of TRUSELTIQ with a gastric acid reducing agent may decrease infigratinib plasma concentrations, which may reduce TRUSELTIQ anti-tumor activity.

Avoid concomitant use of TRUSELTIQ with proton pump inhibitors (PPIs), H2-antagonists, and locally-acting antacids. If coadministration of H2-antagonists or locally-acting antacids cannot be avoided, stagger administration of TRUSELTIQ

BRIEF SUMMARY

INFIGRATINIB- (May 2021)

Indn-  To treat adults with cholangiocarcinoma  whose disease meets certain criteria  

Comp-  Capsules: 25 mg and 100 mg.                                                            Recommended dosage: 125 mg orally once daily for 21 consecutive days followed by 7 days off therapy, in 28-day cycles.

Take on an empty stomach at least 1 hour before or 2 hours after food, at approximately the same time each day.  Swallow capsules whole with a glass of water.

ADR-  Most common adverse reactions were nail toxicity, stomatitis, dry eye, fatigue, alopecia, palmar-plantar erythrodysesthesia syndrome, arthralgia, dysgeusia, constipation, abdominal pain, dry mouth, eyelash changes, diarrhea, dry skin, decreased appetite, vision blurred and vomiting. 

CI- None.

WARNINGS-

 Ocular Toxicity -                                                                                                             can cause retinal pigment epithelial detachment (RPED). Perform comprehensive ophthalmic examination including optical coherence tomography (OCT) prior to initiation of TRUSELTIQ and at 1 month, at 3 months, and then every 3 months thereafter recommended.

Pat Inform-

Ocular Toxicity-                                                                                                           Advise patients that the drug  may cause ocular toxicity including RPED and to immediately inform their healthcare provider if they experience any visual changes.

Advise patients to use artificial tear substitutes or hydrating or lubricating eye gels to prevent or treat dry eyes.

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U.S. FDA APPROVED DRUGS SURING 2021                                          

Serial No 24

Name of the Drug-    TRUSELTIQ

Active Ingredient -   Infrigratinib

Pharmacological Classification-    To treat adults with cholangiocarcinoma                                                                        whose disease meets certain criteria                                                                                                                                                                                                                                                                                                                  Date of Approval-          5/28/2021

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use                              TRUSELTIQ safely and effectively.                                                                               

 See full prescribing information for TRUSELTIQ. TRUSELTIQ (infigratinib) capsules, for oral use

Initial U.S. Approval: 2021

INDICATIONS AND USAGE- 

­ TRUSELTIQ is a kinase inhibitor indicated for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement as detected by an FDA-approved test.

 This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

DOSAGE AND ADMINISTRATION- 

 Confirm the presence of an FGFR2 fusion or rearrangement prior to initiation of treatment with TRUSELTIQ.

 Recommended dosage: 125 mg orally once daily for 21 consecutive days followed by 7 days off therapy, in 28-day cycles.

Take on an empty stomach at least 1 hour before or 2 hours after food, at approximately the same time each day.

 Swallow capsules whole with a glass of water. Do not crush, chew or dissolve.

 Mild and Moderate Renal Impairment: The recommended dosage is 100 mg orally once daily for 21 consecutive days followed by 7 days off therapy, in 28-day cycles.

Mild Hepatic Impairment: The recommended dosage is 100 mg orally once daily for 21 consecutive days followed by 7 days off therapy, in 28-day cycles.

 Moderate Hepatic Impairment: The recommended dosage is 75 mg orally once daily for 21 consecutive days followed by 7 days off therapy, in 28­ day cycles. 

DOSAGE FORMS AND STRENGTHS-

­ Capsules: 25 mg and 100 mg.

CONTRAINDICATION-

­ None.

WARNINGS AND PRECAUTIONS-

 Ocular Toxicity -                                                                                                        TRUSELTIQ can cause retinal pigment epithelial detachment (RPED). Perform comprehensive ophthalmic

ADVERSE REACTIONS

 Most common (=20%) adverse reactions were nail toxicity, stomatitis, dry eye, fatigue, alopecia, palmar-plantar erythrodysesthesia syndrome, arthralgia, dysgeusia, constipation, abdominal pain, dry mouth, eyelash changes, diarrhea, dry skin, decreased appetite, vision blurred and vomiting. 

 Most common laboratory abnormalities (=20%) were increased creatinine, increased phosphate, decreased phosphate, increased alkaline phosphatase, decreased hemoglobin, increased alanine aminotransferase, increased lipase, increased calcium, decreased lymphocytes, decreased sodium, increased triglycerides, increased aspartate aminotransferase, increased urate, decreased platelets, decreased leukocytes, decreased albumin, increased bilirubin and decreased potassium.

CONTRAINDICATION-

­ None.

WARNINGS AND PRECAUTIONS-

 Ocular Toxicity -                                                                                                        TRUSELTIQ can cause retinal pigment epithelial detachment (RPED). Perform comprehensive ophthalmic examination including optical coherence tomography (OCT) prior to initiation of TRUSELTIQ and at 1 month, at 3 months, and then every 3 months thereafter during treatment. Withhold as recommended.

 Hyperphosphatemia and Soft Tissue Mineralization:                                                Increases in phosphate levels can cause hyperphosphatemia leading to soft tissue mineralization, cutaneous calcinosis, non-uremic calciphylaxis, vascular calcification, and myocardial calcification. Withhold, dose reduce, or permanently discontinue as recommended. 

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

DOSAGE AND ADMINISTRATION- 

 Confirm the presence of an FGFR2 fusion or rearrangement prior to initiation of treatment with TRUSELTIQ.

 Recommended dosage: 125 mg orally once daily for 21 consecutive days followed by 7 days off therapy, in 28-day cycles.

Take on an empty stomach at least 1 hour before or 2 hours after food, at approximately the same time each day.

 Swallow capsules whole with a glass of water. Do not crush, chew or dissolve.

 Mild and Moderate Renal Impairment: The recommended dosage is 100 mg orally once daily for 21 consecutive days followed by 7 days off therapy, in 28-day cycles.

Mild Hepatic Impairment: The recommended dosage is 100 mg orally once daily for 21 consecutive days followed by 7 days off therapy, in 28-day cycles.

 Moderate Hepatic Impairment: The recommended dosage is 75 mg orally once daily for 21 consecutive days followed by 7 days off therapy, in 28­ day cycles. 

DOSAGE FORMS AND STRENGTHS-

­ Capsules: 25 mg and 100 mg.

PATIENT COUNSELING INFORMATION

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

Ocular Toxicity-                                                                                                           Advise patients that TRUSELTIQ may cause ocular toxicity including RPED and to immediately inform their healthcare provider if they experience any visual changes.

Advise patients to use artificial tear substitutes or hydrating or lubricating eye gels to prevent or treat dry eyes.

Inform patients that their healthcare provider will closely monitor for eye disorders, with ophthalmic examinations performed by an ophthalmologist, and will manage them as clinically indicated

 Hyperphosphatemia and Soft Tissue Mineralization-                                                     Inform patients that TRUSELTIQ may cause hyperphosphatemia and soft tissue mineralization and to immediately inform their healthcare provider of any symptoms related to acute changes in phosphate levels such as muscle cramps, numbness, or tingling around the mouth

 Nail Disorders -                                                                                                                Advise patients that TRUSELTIQ may cause nail disorders 

 Embryo-Fetal Toxicity-                                                                                                        Advise females to inform their healthcare provider if they are pregnant or become pregnant. Inform females of the risk to a fetus and potential loss of pregnancy

 Advise females of reproductive potential to use effective contraception while on TRUSELTIQ and for 1 month after the final dose

Advise males with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for 1 month after the final dose of TRUSELTIQ

Lactation-                                                                                                                             Advise patients not to breastfeed during treatment with TRUSELTIQ and for 1 month after the final dose.

 Administration-                                                                                                                 Instruct patients to take TRUSELTIQ on an empty stomach at least 1 hour before, or 2 hours after food, at approximately the same time each day. ? Instruct patients to swallow the capsules whole with a glass of water. Advise patients to not crush, chew, or dissolve capsules.

 Instruct patients that if a dose cannot be administered within 4 hours of the regularly scheduled time or if vomiting occurs, the dose should not be made up later that day. Dosing should resume at the usual time on the next day.

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

Advise patients to avoid grapefruit products during treatment with TRUSELTIQ.

Manufactured for: QED Therapeutics, Inc. Brisbane, CA 94005 TRUSELTIQ is a trademark of QED Therapeutics, Inc U.S. Patent Nos. 8,552,002; 9,067,896; 10,278,969 © 2021 QED Therapeutics, Inc. All Rights Reserved Reference ID: 4803321

CLINICAL PHARMACOLOGY-

1.Mechanism of Action-                                                                                                   Infigratinib is a small molecule kinase inhibitor of FGFR with IC50 values of 1.1, 1, 2, and 61 nM for FGFR1, FGFR2, FGFR3, and FGFR4, respectively.

2.Pharmacodynamics- Serum Phosphate TRUSELTIQ increased serum phosphate levels due to FGFR inhibition.

Cardiac Electrophysiology -At the recommended dosing regimen, TRUSELTIQ does not result in a large mean increase (i.e., >20 msec) in the QTc interval.                             

 The QT effect of infigratinib at higher exposures associated with CYP3A inhibition has not been studied.

3.Pharmacokinetics- The infigratinib pharmacokinetic parameters are presented following administration of the approved recommended dosage in cholangiocarcinoma patients, unless otherwise specified.

Effect of Food -Following administration of TRUSELTIQ with a high-fat and high-calorie meal (800 to 1,000 calories with approximately 50% of total caloric content of the meal from fat) in healthy subjects, the mean AUCinf of infigratinib increased by 80%-120% and Cmax increased by 60%-80%, the median Tmax shifted from 4 hours to 6 hours.

Following administration of TRUSELTIQ with a low-fat low-calorie meal (approximately 330 calories with 20% of total caloric content of the meal from fat), the mean AUCinf of infigratinib increased by 70%, Cmax increased by 90%, and the median Tmax did not change.

Distribution- The geometric mean (CV%) apparent volume of distribution of infigratinib was 1600 L (33%) at steady state. The mean infigratinib protein binding was 96.8%, primarily to lipoprotein, and was dependent of drug concentration.

Elimination The geometric mean (CV%) total apparent clearance (CL/F) of infigratinib was 33.1 L/h (59%) at steady state. The geometric mean (CV%) terminal half-life of infigratinib was 33.5 h (39%) at steady state.

Metabolism Infigratinib is predominantly metabolized by CYP3A4 (~94%) and to a lesser extent by FMO3 (6%) in vitro.

Excretion After a single oral 125 mg dose of radiolabeled infigratinib in healthy subjects, approximately 77% of the dose was recovered in feces (3.4% as unchanged) and 7.2% in urine (1.9% as unchanged).

4.Specific Populations No clinically significant differences in the systemic exposure of infigratinib were observed based on age (19-86 years), sex, race/ethnicity (White 70.7%, Black 15.4%, and Asian 8%), or body weight (36.4-169 kg).

5.Patients with Renal Impairment -                                                                                 The relative potency adjusted steady state AUC of infigratinib plus its active metabolites (BHS697, CQM157) in plasma increased by 32% and 37% in patients with mild (creatinine clearance [CLcr] 60 to 89 mL/min estimated by Cockcroft-Gault) and moderate renal impairment (CLcr 30 to 59 mL/min), respectively, relative to patients with normal renal function (CLcr = 90 mL/min).

The effect of severe renal impairment (CLcr < 30 mL/min) or renal dialysis in end-stage renal disease on infigratinib exposure is unknown.

6.Patients with Hepatic Impairment-                                                                            The relative potency adjusted steady state AUC of infigratinib plus its active metabolites (BHS697, CQM157) in plasma increased by 47%-62% and 99% in patients with mild (total bilirubin > upper limit of normal [ULN] to 1.5 × ULN or AST > ULN) and moderate hepatic impairment (total bilirubin > 1.5 to 3 × ULN with any AST), respectively, relative to patients with normal hepatic function (total bilirubin = ULN and AST = ULN).

The effect of severe hepatic impairment (total bilirubin > 3 × ULN with any AST) on infigratinib exposure is unknown 

7.Drug Interaction Studies-                                                                                             Clinical Studies-                                                                                                        Strong CYP3A Inhibitors: Coadministration of multiple doses of itraconazole (strong CYP3A inhibitor) increased infigratinib AUC0-inf by 622% and Cmax by 164%, increased BHS697 AUC0-inf by 174%, and decreased CQM157 Cmax by 69%, respectively [see Drug Interactions (7.1)].

Strong CYP3A Inducers: Coadministration of multiple doses of rifampin (strong CYP3A inducer) decreased infigratinib AUC0-inf by 56% and Cmax by 44%, decreased BHS697 AUC0-inf by 65% and Cmax by 27%, and decreased CQM157 AUC0-inf by 76% and Cmax by 50%, respectively 

Gastric Acid-Lowering Agents:                                                                           Coadministration of multiple doses of lansoprazole (proton pump inhibitor) decreased infigratinib AUC0-inf by 45% and Cmax by 49%, decreased BHS697 AUC0-inf by 32% and Cmax by 44%, and decreased CQM157 AUC0-inf by 72% and Cmax by 55%, respectively. 

CYP3A4 Substrates:                                                                                                           No clinically significant differences in pharmacokinetics of midazolam (sensitive CYP3A4 substrate) were observed when co-administered with TRUSELTIQ

 USE IN SPECIFIC POPULATIONS

1.Pregnancy Risk Summary-                                                                                            Based on findings in animal studies and its mechanism of action TRUSELTIQ can cause fetal harm or loss of pregnancy when administered to a pregnant woman

There are no available data on the use of TRUSELTIQ during pregnancy.

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 on the presence of infigratinib or its metabolites in human milk, or their effects on either the breastfed child or on milk production.

Because of the potential for serious adverse reactions in breastfed children from TRUSELTIQ, advise women not to breastfeed during treatment and for 1 month after the final dose. Reference ID: 4803321

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

Pregnancy Testing -Verify pregnancy status of females of reproductive potential prior to initiating TRUSELTIQ.

Contraception Females Advise females of reproductive potential to use effective contraception during treatment with TRUSELTIQ and for 1 month after the final dose.

Males- Advise males that are partnered with females of reproductive potential to use effective contraception during treatment with TRUSELTIQ and for 1 month after the final dose.

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

5.Geriatric Use-                                                                                                                       Of the 351 patients treated with TRUSELTIQ in clinical studies, 33% were 65 years or older, and 10% were 75 years or older. No overall differences in safety or effectiveness of TRUSELTIQ have been observed between patients 65 years of age and older and younger adult patients.

6.Patients with Renal Impairment-                                                                                        Reduce the dosage of TRUSELTIQ for patients with mild or moderate renal impairment (creatinine clearance [CLcr] 30 to 89 mL/min estimated by Cockcroft-Gault).

The recommended dosage of TRUSELTIQ has not been established for patients with severe renal impairment (CLcr < 30 mL/min) or for patients with end-stage renal disease receiving intermittent hemodialysis.

7.Patients with Hepatic Impairment-                                                                                  Reduce the dosage of TRUSELTIQ for patients with mild (total bilirubin > upper limit of normal [ULN] to 1.5 × ULN or AST > ULN) or moderate (total bilirubin >1.5 to 3 × ULN with any AST) hepatic impairment.

The recommended dosage of TRUSELTIQ has not been established in patients with severe (total bilirubin > 3 × ULN with any AST) hepatic impairment

.