DRUG INTERACTIONS-(summary)

 • Dual P-gp and strong CYP3A inhibitors: Avoid coadministration.

 • Dual P-gp and strong CYP3A inducers: Avoid coadministration.

DRUG INTERACTIONS-(details)-

1. Effect of Other Drugs on LYTGOBI-                                                                                Futibatinib is a substrate of CYP3A and P-gp. Dual P-gp and Strong CYP3A Inhibitors Avoid concomitant use of drugs that are dual P-gp and strong CYP3A inhibitors with LYTGOBI.

Concomitant use of drugs that are dual P-gp and strong CYP3A inhibitors with LYTGOBI may increase futibatinib exposure , which may increase the incidence and severity of adverse reactions.

Dual P-gp and Strong CYP3A Inducers-                                                                   Avoid concomitant use of dual P-gp and strong CYP3A inducers with LYTGOBI. Concomitant use of drugs that are dual P-gp and strong CYP3A inducers may decrease futibatinib exposure , which may reduce the efficacy of LYTGOBI.

2. Effect of LYTGOBI on Other Drugs-                                                                         Futibatinib is an inhibitor of P-gp and BCRP. P-gp or BCRP Substrates: Consider more frequent monitoring for adverse reactions associated with concomitantly administered drugs that are sensitive substrates of P-gp or BCRP and reduce the dose of these

 Futibatinib may increase exposure of drugs that are substrates of P-gp or BCRP.

BRIEF SUMMARY

FUTIBATINAB- (Sep 2022)

Indn- To treat intrahepatic carcinoma  harbouring  fibroblast   Growth factor 2 (FGFRZ) Gene fusions or other  rearrangement   

Comp- Tablets: 4 mg  Recommended dose is 20 mg orally (five 4 mg tablets) once daily until disease progression or unacceptable toxicity occurs.

  Swallow tablet whole, with or without food.

ADR- Most common (=20%) adverse reactions were nail toxicity, musculoskeletal pain, constipation, diarrhea, fatigue, dry mouth, alopecia, stomatitis, abdominal pain, dry skin, arthralgia, dysgeusia, dry eye, nausea, decreased appetite, urinary tract infection

CI- None

WARNINGS-

 can cause retinal pigment epithelial detachment (RPED). Perform a comprehensive ophthalmological examination including optical coherence tomography (OCT) prior to initiation of therapy, every 2 months for the first 6 months, and every 3 months thereafter and urgently at any time for visual symptoms.

Increases in phosphate levels can cause hyperphosphatemia leading to soft tissue mineralization, calcinosis, nonuremic calciphylaxis and vascular calcification.

Pat inform-

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

Advise patients to use artificial tears, or hydrating or lubricating eye gels to prevent or treat dry eyes

==================================================================

U.S.  APPROVED DRUGS SURING 2022                                        

Serial No 26

Name-        LYTGOBL 

Active  Ingredient -  Futibatinab

Pharmacological clssificiation-        To treat intrahepatic carcinoma  harbouring                                                                   fibroblast   Growth factor 2 (FGFRZ) Gene                                                                     fusions or other  rearrangement                                                                                                                                                                    Date of Approval-         9/30/2022    

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use LYTGOBI safely and effectively. See full prescribing information for LYTGOBI. LYTGOBI® (futibatinib) tablets, for oral use

Initial U.S. Approval: 2022

INDICATIONS AND USAGE-

 LYTGOBI is a kinase inhibitor indicated for the treatment of adult patients with previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma harboring fibroblast growth factor receptor 2 (FGFR2) gene fusions or other rearrangements.

 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 a confirmatory trial(s).

ADVERSE REACTIONS-

 • Most common (=20%) adverse reactions were nail toxicity, musculoskeletal pain, constipation, diarrhea, fatigue, dry mouth, alopecia, stomatitis, abdominal pain, dry skin, arthralgia, dysgeusia, dry eye, nausea, decreased appetite, urinary tract infection, palmar-plantar erythrodysesthesia syndrome, and vomiting.

 • Most common laboratory abnormalities (=20%) were increased phosphate, increased creatinine, decreased hemoglobin, increased glucose, increased calcium, decreased sodium, decreased phosphate, increased alanine aminotransferase, increased alkaline phosphatase, decreased lymphocytes, increased aspartate aminotransferase, decreased platelets, increased activated partial thromboplastin time, decreased leukocytes, decreased albumin, decreased neutrophils, increased creatine kinase, increased bilirubin, decreased glucose, increased prothrombin international normalized ratio, and decreased potassium.

CONTRAINDICATIONS-

 None

WARNINGS AND PRECAUTIONS-

 • Ocular Toxicity: LYTGOBI can cause retinal pigment epithelial detachment (RPED). Perform a comprehensive ophthalmological examination including optical coherence tomography (OCT) prior to initiation of therapy, every 2 months for the first 6 months, and every 3 months thereafter and urgently at any time for visual symptoms.

 • Hyperphosphatemia and Soft Tissue Mineralization:                                            Increases in phosphate levels can cause hyperphosphatemia leading to soft tissue mineralization, calcinosis, nonuremic calciphylaxis and vascular calcification.

Monitor for hyperphosphatemia and withhold, reduce the dose, or permanently discontinue based on duration and severity of hyperphosphatemia.

 • 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 gene fusion or other rearrangement prior to initiation of treatment with LYTGOBI.

 • Recommended dose is 20 mg orally (five 4 mg tablets) once daily until disease progression or unacceptable toxicity occurs.

 • Swallow tablet whole, with or without food.

DOSAGE FORMS AND STRENGTHS-

 Tablets: 4 mg 

PATIENT COUNSELING INFORMATION

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

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

Advise patients to use artificial tears, or hydrating or lubricating eye gels to prevent or treat dry eyes

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

Nail Disorders- Advise patients that LYTGOBI may cause nail disorders.

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

• Advise females of reproductive potential to use effective contraception while on LYTGOBI and for 1 week after the last dose.

. • Advise males with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for 1 week after receiving the last dose of LYTGOB. 

Lactation -                                                                                                                          • Advise patients not to breastfeed during treatment with LYTGOBI and for 1 week after the last dose.

• Instruct patients to not crush, chew, split or dissolve tablets.

• Instruct patients if they miss a dose by 12 or more hours or if they vomit after taking a dose, resume dosing with the next scheduled dose. Extra tablets should not be taken to make up for the missed dose.

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 LYTGOBI.

Manufactured for: Taiho Pharmaceutical Co., Ltd. Japan Distributed by: Taiho Oncology, Inc. Princeton, NJ 08540 USA LYTGOBI is a trademark of Taiho Pharmaceutical Co., Ltd. U.S. Patent Nos. 9,108,973 and 10,434,103 © 2022 Taiho Oncology, Inc. All rights reserved.

CLINICAL PHARMACOLOGY-

1. Mechanism of Action-                                                                                    Futibatinib is a small molecule kinase inhibitor of FGFR 1, 2, 3, and 4 with IC50 values of less than 4 nM. Futibatinib covalently binds FGFR. Constitutive FGFR signaling can support the proliferation and survival of malignant cells.

Futibatinib inhibited FGFR phosphorylation and downstream signaling and decreased cell viability in cancer cell lines with FGFR alterations including FGFR fusions/rearrangements, amplifications, and mutations.

Futibatinib demonstrated anti-tumor activity in mouse and rat xenograft models of human tumors with activating FGFR genetic alterations.

2. Pharmacodynamics-                                                                                                    Serum Phosphate Futibatinib increased serum phosphate levels due to FGFR inhibition. Serum phosphate increased with increasing futibatinib exposure across the dose range of 4 to 24 mg orally once daily (0.2 to 1.2 times the recommended dose), with increased risk of hyperphosphatemia at higher futibatinib exposure.

Cardiac Electrophysiology-                                                                                             At four times the approved recommended dose, LYTGOBI does not cause clinically significant QTc interval prolongation.

3. Pharmacokinetics-                                                                                                        The pharmacokinetics of futibatinib administered 20 mg once daily were evaluated in patients with advanced solid tumors unless otherwise specified.

Futibatinib exposure (AUC) increased proportionally over the dose range from 4 to 24 mg orally once daily (0.2 to 1.2 times the maximum approved recommended dosage).

At the recommended dosage, the geometric mean (coefficient of variation [CV] %) maximal concentration of futibatinib at steady state (Cmax,ss) was 144 ng/mL (50%) and AUC at steady state (AUCss) was 790 ng·hr/mL (45%), with no accumulation after repeat doses.

Absorption-                                                                                                                  Median time to reach maximum futibatinib plasma concentration (Tmax) was 2 (range: 1.2 to 22.8) hours.

Effect of Food-                                                                                                       Administration of LYTGOBI with a high-fat and high-calorie meal (900 to 1000 calories with approximately 50% of total caloric content from fat) decreased futibatinib AUC by 11% and Cmax by 42% in healthy subjects.

Distribution-                                                                                                                  The geometric mean (CV%) apparent volume of distribution (Vc/F) is 66 L (18%). Futibatinib is 95% bound to human plasma protein at 0.2 to 5 µmol/L in vitro, primarily to albumin and a1-acid glycoprotein

 Elimination-                                                                                                                     The mean (CV%) elimination half-life (T1/2) of futibatinib is 2.9 hours (27%) and the geometric mean (CV%) apparent clearance (CL/F) is 20 L/h (23%).

Metabolism-                                                                                                                 Futibatinib is primarily metabolized by CYP3A and to a lesser extent by CYP2C9 and CYP2D6 in vitro. Unchanged futibatinib is the major drug-related moiety in plasma (59% of radioactivity) in healthy subjects.

Excretion-                                                                                                                     Following a single oral dose of 20 mg radiolabeled futibatinib, approximately 91% of the total recovered radioactivity was observed in feces and 9% in urine, with negligible unchanged futibatinib in urine or feces.

Specific Populations-                                                                                                    No clinically meaningful differences in the systemic exposure of futibatinib were observed based on age (18 - 82 years), sex, race (White, Asian, and African American), body weight (36 - 152 kg), mild to moderate renal impairment (creatinine clearance [CLcr] 30 - 89 mL/min estimated by Cockcroft-Gault), or mild hepatic impairment (total bilirubin = upper limit of normal (ULN) and aspartate transaminase (AST) > ULN, or total bilirubin >1 to 1.5? ULN and any AST). 

The pharmacokinetics of futibatinib has not been studied in patients with severe renal impairment (CLcr 15 - 29 mL/min), renal dialysis in end-stage renal disease (CLcr <15 mL/min), or moderate or severe hepatic impairment (total bilirubin >1.5? ULN and any AST).

Drug Interaction Studies-                                                                                             Clinical Studies Effect of Other Drugs on Futibatinib Dual P-gp and strong CYP3A inhibitors:                                                                                                                        Co-administration of multiple doses of itraconazole (P-gp and strong CYP3A inhibitor) increased single dose futibatinib Cmax by 51% and AUC by 41%

 Dual P-gp and strong CYP3A inducers:                                                                             Co-administration of multiple doses of rifampin (P-gp and strong CYP3A inducer) decreased single dose futibatinib Cmax by 53% and AUC by 64%..

The effect of a P-gp modulator (without CYP3A modulation), or a strong CYP3A modulator (without P-gp modulation) on the exposure of futibatinib has not been investigated.

Gastric acid reducing agents: Co-administration of multiple doses of lansoprazole (proton pump inhibitor) had no effect on single dose futibatinib AUC.

Effect of Futibatinib On Other Drugs CYP3A substrates: Co-administration of multiple doses of futibatinib had no effect on single dose midazolam (sensitive CYP3A substrate) AUC.

In Vitro Studies-                                                                                                              Effect of Transporters on Futibatinib: Futibatinib is a substrate for P-gp and BCRP, but not for OATP1B1 or OATP1B3.

Effect of Futibatinib on CYP Enzymes:                                                                     Futibatinib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A, and does not induce CYP1A2, CYP2B6 or CYP3A4 at clinically relevant concentrations.

Effect of Futibatinib on Transporter Systems:                                                         Futibatinib inhibits P-gp and BCRP, but does not inhibit OAT1, OAT3, OCT2, OATP1B1, OATP1B3, MATE1, or MATE2K at clinically relevant concentrations.

 USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary-

Based on findings in an animal study and its mechanism of action, LYTGOBI can cause fetal harm or loss of pregnancy when administered to a pregnant woman [see Clinical Pharmacology (12.1)].

There are no available data on the use of LYTGOBI in pregnant women. Oral administration of futibatinib to pregnant rats during the  period of organogenesis at maternal plasma exposures below the human exposure at the clinical dose of 20 mg resulted in fetal malformations, fetal growth retardation, and embryo-fetal death

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 futibatinib 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 from LYTGOBI in breastfed children, advise women not to breastfeed during treatment and for 1 week after the last dose.

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

Pregnancy Testing Verify pregnancy status of females of reproductive potential prior to initiating LYTGOBI ].

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

Males-                                                                                                                           Advise males with female partners of reproductive potential or who are pregnant to use effective contraception during treatment with LYTGOBI and for 1 week after the last dose.

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

Animal Toxicity- Data In 4- or 13-week repeat-dose toxicology studies in adult rats and dogs, findings included increased inorganic  phosphorus and calcium in plasma, ectopic mineralization in various organs and tissues, and lesions in bone/cartilage at futibatinib exposures lower than the human exposure at the clinical dose of 20 mg.

Findings in rats also included corneal lesions. Evidence of recovery in rats and dogs was observed four weeks after cessation of dosing except for the ectopic mineralization.

4.Geriatric Use-                                                                                                               Of the 103 patients treated with LYTGOBI in Study TAS-120-101, 22% were 65 years or older. Based on available data, no overall differences in safety or effectiveness of LYTGOBI have been observed between patients 65 years of age and older and younger adult patients.