oderate cyp3a inducers. gastric acid reducing agents the coadministration of truseltiq with a gastric acid reducing agent may decrease infigratinib plasma concentrations [ see clinical pharmacology ( 12.3 ) ], 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 [ see dosage and administration ( 2.4 ) ].

nd locally-acting antacids. if coadministration of h2-antagonists or locally-acting antacids cannot be avoided, stagger administration of truseltiq [ see dosage and administration ( 2.4 ) ].

ponse. continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). ( 1 )

among 351 patients who received truseltiq across clinical trials [ see adverse reactions ( 6.1 ) ] where ophthalmologic monitoring did not routinely include optical coherence tomography (oct), rped occurred in 11% of patients, including patients with asymptomatic rped. the median time to first onset of rped was 26 days. rped led to dose interruption/reduction of truseltiq in 3.4% of patients, and permanent discontinuation in 0.6% of patients. perform a comprehensive ophthalmic examination including oct prior to initiation of truseltiq, at 1 month, at 3 months, and then every 3 months thereafter during treatment. refer patients for ophthalmic evaluation urgently for onset of visual symptoms, and follow-up every 3 weeks until resolution or discontinuation of truseltiq. withhold truseltiq as recommended [ see dosage and administration ( 2.3 ), adverse reactions ( 6.1 ) ]. dry eye among 351 patients who received truseltiq across clinical trials [ see adverse reactions ( 6.1 ) ], dry eye occurred in 29% of patients. treat patients with ocular demulcents as needed. 5.2 hyperphosphatemia and soft tissue mineralization truseltiq can cause hyperphosphatemia leading to soft tissue mineralization, cutaneous calcinosis, non-uremic calciphylaxis, vascular calcification, and myocardial calcification. increases in phosphate levels are a pharmacodynamic effect of truseltiq [ see clinical pharmacology ( 12.2 ) ]. among 351 patients who received truseltiq across clinical trials [ see adverse reactions ( 6.1 ) ], hyperphosphatemia was reported in 82% of patients based on laboratory values above the upper limit of normal. the median time to onset of hyperphosphatemia was 8 days (range 1-349). phosphate binders were received by 83% of patients who received truseltiq. monitor for hyperphosphatemia throughout treatment. initiate phosphate lowering therapy when serum phosphate level is >5.5 mg/dl. for serum phosphate level >7.5 mg/dl, withhold truseltiq and initiate phosphate lowering therapy. withhold, dose reduce, or permanently discontinue truseltiq based on duration and severity of hyperphosphatemia [ see dosage and administration ( 2.3 ) ]. 5.3 embryo-fetal toxicity based on findings in animal studies and its mechanism of action, truseltiq can cause fetal harm when administered to a pregnant woman. oral administration of infigratinib to pregnant animals during the period of organogenesis caused malformations, fetal growth retardation, and embryo-fetal death at maternal exposures lower than the human exposure based on area under the curve (auc) at the clinical dose of 125 mg. advise pregnant women of the potential risk to the fetus. advise females of reproductive potential to use effective contraception during treatment with truseltiq and for 1 month after the final dose. advise males with female partners of reproductive potential to use effective contraception during treatment with truseltiq and for 1 month after the final dose [ see use in specific populations ( 8.1 , 8.3 ) ].

reactions ( 6.1 ) ]. dry eye among 351 patients who received truseltiq across clinical trials [ see adverse reactions ( 6.1 ) ], dry eye occurred in 29% of patients. treat patients with ocular demulcents as needed.

ration and severity of hyperphosphatemia [ see dosage and administration ( 2.3 ) ].

s for the treatment of unresectable locally advanced or metastatic cholangiocarcinoma with truseltiq based on the presence of an fgfr2 fusion or rearrangement, as detected by an fda-approved test [ see clinical studies ( 14.1 ) ]. information on fda-approved test(s) for the detection of fgfr2 fusions or rearrangements in cholangiocarcinoma is available at: http://www.fda.gov/companiondiagnostics. 2.2 recommended dosage the recommended dosage of truseltiq is 125 mg (one 100 mg capsule and one 25 mg capsule) orally once daily for 21 consecutive days followed by 7 days off therapy, in 28-day cycles. continue treatment until disease progression or unacceptable toxicity. instruct patients to take truseltiq on an empty stomach at least 1 hour before or 2 hours after food [ see clinical pharmacology ( 12.3 ) ], at approximately the same time each day. instruct patients to swallow capsules whole with a glass of water. advise patients to not crush, chew, or dissolve capsules. if a dose of truseltiq is missed by ≥4 hours or if vomiting occurs, instruct patients to resume the regular daily dose schedule for truseltiq the next day. 2.3 dose modification for adverse reactions the recommended dose reductions for adverse reactions are listed in table 1. table 1: recommended dose reduction for truseltiq for adverse reactions 1 st dose reduction 2 nd dose reduction 3 rd dose reduction 100 mg (one 100 mg capsule) 75 mg (three 25 mg capsules) 50 mg (two 25 mg capsules) the recommended dosage modifications for adverse reactions are provided in table 2 . table 2: recommended dosage modifications for truseltiq adverse reactions adverse reaction severity a truseltiq dose modifications retinal pigment epithelial detachment (rped) [ see warnings and precautions ( 5.1 ) ] not applicable continue truseltiq at the current dose and continue periodic ophthalmic evaluation: if resolving within 14 days, continue truseltiq at the current dose. if not resolving within 14 days, withhold truseltiq until resolving; then resume truseltiq at previous or a lower dose. hyperphosphatemia [ see warnings and precautions ( 5.2 ) ] serum phosphate >5.5 – ≤7.5 mg/dl continue truseltiq at the current dose and initiate or dose adjust phosphate binder according to respective label. monitor serum phosphate weekly. phosphate binder dosing should be held during the week off truseltiq therapy each cycle (days 22-28) and during truseltiq dose interruptions for non-hyperphosphatemia adverse events. serum phosphate >7.5 mg/dl or single serum phosphate >9 mg/dl regardless of duration or dose of phosphate lowering therapy. withhold truseltiq until level returns to serum phosphate ≤5.5 mg/dl. resume truseltiq as below, with maximal phosphate binder dosing: if serum phosphate >7.5 mg/dl occurred for less than 7 days: restart truseltiq at the same dose. if serum phosphate >7.5 mg/dl for >7 days or if patient had a one-time serum phosphate of >9 mg/dl: resume truseltiq at the next lower dose level. serum phosphate with life-threatening consequences; urgent intervention indicated (e.g., dialysis) permanently discontinue truseltiq. other adverse reactions grade 3 withhold dose of truseltiq until resolved to grade ≤1, then resume at the next lower dose level of truseltiq. if not resolved within ≤14 days, permanently discontinue truseltiq. grade 4 permanently discontinue truseltiq. a severity as defined by national cancer institute common terminology criteria for adverse events (nci ctcae version 4.03). 2.4 dose modification for moderate hepatic impairment avoid coadministration of a proton pump inhibitor (ppi), a histamine-2 (h2) receptor antagonist, or a locally-acting antacid with truseltiq [ see drug interactions ( 7.1 ) ]. if coadministration cannot be avoided: h2-antagonist: separate administration of truseltiq by 2 hours before or 10 hours after. locally-acting antacid: separate administration of truseltiq by 2 hours before or after. 2.5 recommended dosage for mild and moderate renal impairment the recommended dosage of truseltiq for patients with mild to moderate renal impairment (creatinine clearance 30 to 89 ml/min, estimated by cockcroft-gault) is 100 mg once daily for 21 consecutive days followed by 7 days off therapy, in 28-day cycles [ see use in specific population ( 8.6 ), clinical pharmacology ( 12.3 ) ]. 2.6 recommended dosage for mild and moderate hepatic impairment the recommended dosage of truseltiq for patients with mild (total bilirubin > upper limit of normal [uln] to 1.5 × uln or ast > uln ) or moderate hepatic impairment (total bilirubin >1.5 to 3 × uln with any ast) is as follows [ see use in specific population ( 8.7 ), clinical pharmacology ( 12.3 ) ]. mild hepatic impairment: 100 mg once daily for 21 consecutive days followed by 7 days off therapy, in 28-day cycles. moderate hepatic impairment: 75 mg once daily for 21 consecutive days followed by 7 days off therapy, in 28-day cycles.

e >5.5 – ≤7.5 mg/dl continue truseltiq at the current dose and initiate or dose adjust phosphate binder according to respective label. monitor serum phosphate weekly. phosphate binder dosing should be held during the week off truseltiq therapy each cycle (days 22-28) and during truseltiq dose interruptions for non-hyperphosphatemia adverse events. serum phosphate >7.5 mg/dl or single serum phosphate >9 mg/dl regardless of duration or dose of phosphate lowering therapy. withhold truseltiq until level returns to serum phosphate ≤5.5 mg/dl. resume truseltiq as below, with maximal phosphate binder dosing: if serum phosphate >7.5 mg/dl occurred for less than 7 days: restart truseltiq at the same dose. if serum phosphate >7.5 mg/dl for >7 days or if patient had a one-time serum phosphate of >9 mg/dl: resume truseltiq at the next lower dose level. serum phosphate with life-threatening consequences; urgent intervention indicated (e.g., dialysis) permanently discontinue truseltiq. other adverse reactions grade 3 withhold dose of truseltiq until resolved to grade ≤1, then resume at the next lower dose level of truseltiq. if not resolved within ≤14 days, permanently discontinue truseltiq. grade 4 permanently discontinue truseltiq. a severity as defined by national cancer institute common terminology criteria for adverse events (nci ctcae version 4.03).

reased potassium. ( 6.1 ) to report suspected adverse reactions, contact qed therapeutics, inc. at 1-844-550-bbio (2246) 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. the pooled safety population described in the warnings and precautions reflect exposure to truseltiq as a single agent at 125 mg orally once daily for 21 consecutive days followed by 7 days off therapy, in 28-day cycles in 351 patients in study cbgj398x2204 and in patients with other advanced solid tumors or hematological malignancies. among 351 patients who received truseltiq, 27% were exposed for 6 months or longer and 10% were exposed for greater than one year. previously treated, unresectable locally advanced or metastatic cholangiocarcinoma the safety of truseltiq was evaluated in study cbgj398x2204, which included 108 patients with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with an fgfr2 fusion or other rearrangement [ see clinical studies ( 14.1 ) ]. patients were treated orally with truseltiq 125 mg once daily for 21 consecutive days followed by 7 days off therapy, in 28-day cycles, until disease progression or unacceptable toxicity. the median duration of treatment was 5.5 months (range: 0.03 to 28.3 months). the median age of truseltiq treated patients was 53 years (range 23-81), 62% were females, and 72% were white. serious adverse reactions occurred in 32% of patients receiving truseltiq. serious adverse reactions in ≥2% of patients who received truseltiq included infections, anemia, pyrexia, abdominal pain, hypercalcemia, and sepsis. fatal adverse reactions occurred in 1 (0.9%) patient who received truseltiq and was due to sepsis. permanent discontinuation due to an adverse reaction occurred in 15% of patients who received truseltiq. adverse reactions requiring permanent discontinuation in ≥1% of patients were blood creatinine increased, fatigue, subretinal fluid, and calcinosis. dosage interruptions due to an adverse reaction occurred in 64% of patients who received truseltiq. adverse reactions requiring dosage interruption in ≥5% of patients included hyperphosphatemia, hypercalcemia, palmar-plantar erythrodysesthesia syndrome, stomatitis, diarrhea, and blood creatinine increased. dosage reductions due to an adverse reaction occurred in 60% of patients who received truseltiq. adverse reactions requiring dosage reductions in ≥2% of patients who received truseltiq included hyperphosphatemia, stomatitis, palmar-plantar erythrodysesthesia syndrome, increased blood creatinine, increased lipase, hypercalcemia, and onycholysis. the 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. the 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. table 3 summarizes the adverse reactions in study cbgj398x2204. table 4 summarizes select laboratory abnormalities in study cbgj398x2204. table 3: adverse reactions (≥15%) in patients receiving truseltiq in study cbgj398x2204 truseltiq n=108 adverse reaction all grades (%) grades 3 or 4 a (%) skin and subcutaneous tissue disorders nail toxicity b 57 2* alopecia 38 0 palmar-plantar erythrodysesthesia syndrome 33 7* dry skin 23 0 gastrointestinal disorders stomatitis c 56 15* constipation 30 1* abdominal pain d 26 5* dry mouth 25 0 diarrhea 24 3* vomiting 21 1* nausea 19 1* dyspepsia 17 0 eye disorders e dry eye f 44 0 eyelash changes g 25 0 vision blurred 21 0 general disorders and administrative site conditions fatigue h 44 4* edema i 17 1* pyrexia 15 1* musculoskeletal and connective tissue disorders arthralgia 32 0 pain in extremity 17 2* nervous system disorders dysgeusia 32 0 headache 17 1* metabolism and nutrition disorders decreased appetite 22 1* respiratory, thoracic and mediastinal disorders epistaxis 18 0 investigations weight decreased 15 2* graded according to national cancer institute common terminology criteria for adverse events (nci ctcae 4.03). a events of grade 3 only (no grade 4 occurred) are marked with an asterisk. b includes ingrown nail, nail bed bleeding, nail bed disorder, nail bed inflammation, nail bed tenderness, nail discoloration, nail disorder, nail dystrophy, nail hypertrophy, nail infection, nail ridging, onychalgia, onychoclasis, onycholysis, onychomadesis, onychomycosis, and paronychia. c includes mouth ulceration and stomatitis. d includes abdominal pain, abdominal pain upper, abdominal discomfort, and abdominal pain lower. e severity of eye disorders is not represented by ctcae grading f includes dry eye, keratitis, lacrimation increased, pinguecula, and punctate keratitis. g includes blepharitis, eyelash changes, eyelash discoloration, growth of eyelashes, trichiasis, and trichomegaly. h includes asthenia and fatigue. i includes edema peripheral and edema. clinically relevant adverse reactions occurring in ≤15% of patients included cataracts (12%) and fractures (1%). table 4: select laboratory abnormalities (≥10%) worsening from baseline in patients receiving truseltiq in study cbgj398x2204 truseltiq n=108 laboratory abnormality all grades (%) grade 3 or 4 (%) hematology decreased hemoglobin 53 5 decreased lymphocytes 43 9 decreased platelets 37 4 decreased leukocytes 26 3 decreased neutrophils 14 2 chemistry increased creatinine 93 7 increased phosphate a 90 13 decreased phosphate 64 31 increased alkaline phosphatase 54 8 increased alanine aminotransferase 51 6 increased lipase 44 7 increased calcium 43 7 decreased sodium 41 20 increased triglycerides 38 3 increased aspartate aminotransferase 38 4 increased urate 37 37 decreased albumin 24 1 increased bilirubin 24 6 decreased potassium 21 3 increased cholesterol 18 1 increased potassium 17 3 decreased calcium 10 2 the denominator used to calculate the rate varied from 104 to 107 based on the number of patients with a baseline value and at least one post-treatment value. these laboratory abnormalities are values that reflect worsening from baseline. graded per nci ctcae 4.03. a nci ctcae 4.03 does not define grades for increased phosphate. laboratory value shift table categories were used to assess increased phosphorus levels (grades ≥3 defined as ≥9mg/dl).

atic cholangiocarcinoma with an fgfr2 fusion or other rearrangement [ see clinical studies ( 14.1 ) ]. patients were treated orally with truseltiq 125 mg once daily for 21 consecutive days followed by 7 days off therapy, in 28-day cycles, until disease progression or unacceptable toxicity. the median duration of treatment was 5.5 months (range: 0.03 to 28.3 months). the median age of truseltiq treated patients was 53 years (range 23-81), 62% were females, and 72% were white. serious adverse reactions occurred in 32% of patients receiving truseltiq. serious adverse reactions in ≥2% of patients who received truseltiq included infections, anemia, pyrexia, abdominal pain, hypercalcemia, and sepsis. fatal adverse reactions occurred in 1 (0.9%) patient who received truseltiq and was due to sepsis. permanent discontinuation due to an adverse reaction occurred in 15% of patients who received truseltiq. adverse reactions requiring permanent discontinuation in ≥1% of patients were blood creatinine increased, fatigue, subretinal fluid, and calcinosis. dosage interruptions due to an adverse reaction occurred in 64% of patients who received truseltiq. adverse reactions requiring dosage interruption in ≥5% of patients included hyperphosphatemia, hypercalcemia, palmar-plantar erythrodysesthesia syndrome, stomatitis, diarrhea, and blood creatinine increased. dosage reductions due to an adverse reaction occurred in 60% of patients who received truseltiq. adverse reactions requiring dosage reductions in ≥2% of patients who received truseltiq included hyperphosphatemia, stomatitis, palmar-plantar erythrodysesthesia syndrome, increased blood creatinine, increased lipase, hypercalcemia, and onycholysis. the 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. the 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. table 3 summarizes the adverse reactions in study cbgj398x2204. table 4 summarizes select laboratory abnormalities in study cbgj398x2204. table 3: adverse reactions (≥15%) in patients receiving truseltiq in study cbgj398x2204 truseltiq n=108 adverse reaction all grades (%) grades 3 or 4 a (%) skin and subcutaneous tissue disorders nail toxicity b 57 2* alopecia 38 0 palmar-plantar erythrodysesthesia syndrome 33 7* dry skin 23 0 gastrointestinal disorders stomatitis c 56 15* constipation 30 1* abdominal pain d 26 5* dry mouth 25 0 diarrhea 24 3* vomiting 21 1* nausea 19 1* dyspepsia 17 0 eye disorders e dry eye f 44 0 eyelash changes g 25 0 vision blurred 21 0 general disorders and administrative site conditions fatigue h 44 4* edema i 17 1* pyrexia 15 1* musculoskeletal and connective tissue disorders arthralgia 32 0 pain in extremity 17 2* nervous system disorders dysgeusia 32 0 headache 17 1* metabolism and nutrition disorders decreased appetite 22 1* respiratory, thoracic and mediastinal disorders epistaxis 18 0 investigations weight decreased 15 2* graded according to national cancer institute common terminology criteria for adverse events (nci ctcae 4.03). a events of grade 3 only (no grade 4 occurred) are marked with an asterisk. b includes ingrown nail, nail bed bleeding, nail bed disorder, nail bed inflammation, nail bed tenderness, nail discoloration, nail disorder, nail dystrophy, nail hypertrophy, nail infection, nail ridging, onychalgia, onychoclasis, onycholysis, onychomadesis, onychomycosis, and paronychia. c includes mouth ulceration and stomatitis. d includes abdominal pain, abdominal pain upper, abdominal discomfort, and abdominal pain lower. e severity of eye disorders is not represented by ctcae grading f includes dry eye, keratitis, lacrimation increased, pinguecula, and punctate keratitis. g includes blepharitis, eyelash changes, eyelash discoloration, growth of eyelashes, trichiasis, and trichomegaly. h includes asthenia and fatigue. i includes edema peripheral and edema. clinically relevant adverse reactions occurring in ≤15% of patients included cataracts (12%) and fractures (1%). table 4: select laboratory abnormalities (≥10%) worsening from baseline in patients receiving truseltiq in study cbgj398x2204 truseltiq n=108 laboratory abnormality all grades (%) grade 3 or 4 (%) hematology decreased hemoglobin 53 5 decreased lymphocytes 43 9 decreased platelets 37 4 decreased leukocytes 26 3 decreased neutrophils 14 2 chemistry increased creatinine 93 7 increased phosphate a 90 13 decreased phosphate 64 31 increased alkaline phosphatase 54 8 increased alanine aminotransferase 51 6 increased lipase 44 7 increased calcium 43 7 decreased sodium 41 20 increased triglycerides 38 3 increased aspartate aminotransferase 38 4 increased urate 37 37 decreased albumin 24 1 increased bilirubin 24 6 decreased potassium 21 3 increased cholesterol 18 1 increased potassium 17 3 decreased calcium 10 2 the denominator used to calculate the rate varied from 104 to 107 based on the number of patients with a baseline value and at least one post-treatment value. these laboratory abnormalities are values that reflect worsening from baseline. graded per nci ctcae 4.03. a nci ctcae 4.03 does not define grades for increased phosphate. laboratory value shift table categories were used to assess increased phosphorus levels (grades ≥3 defined as ≥9mg/dl).

oderate cyp3a inducers. gastric acid reducing agents the coadministration of truseltiq with a gastric acid reducing agent may decrease infigratinib plasma concentrations [ see clinical pharmacology ( 12.3 ) ], 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 [ see dosage and administration ( 2.4 ) ].

nd locally-acting antacids. if coadministration of h2-antagonists or locally-acting antacids cannot be avoided, stagger administration of truseltiq [ see dosage and administration ( 2.4 ) ].

l lethality at 10 mg/kg/day and reductions in fetal body weights at ≥3 mg/kg/day (<0.1 times the human exposure at the clinical dose of 125 mg). fetal abnormalities (external, soft tissue, and skeletal) were increased at ≥1 mg/kg/day (<0.1 times the human exposure at the clinical dose of 125 mg). in the embryo-fetal portion of a rat fertility study, infigratinib decreased the mean number of embryos and increased nonviable embryos and post-implantation loss in females at 3 mg/kg/day. once daily oral administration of infigratinib at ≥0.3 mg/kg/day to pregnant rabbits resulted in maternal toxicity and a corresponding reduction in fetal body weights. 8.2 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. 8.3 females and males of reproductive potential truseltiq can cause fetal harm when administered to a pregnant woman [ see use in specific populations ( 8.1 ) ]. 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. 8.4 pediatric use the safety and effectiveness of truseltiq in pediatric patients have not been established. animal toxicity data in rat and dog repeat-dose toxicity studies ≥13 weeks in duration, animals displayed toxicities in bones (rats and dogs) and teeth (rats) at exposures lower than the human exposure at the clinical dose of 125 mg. once daily oral administration of infigratinib in a 13-week rat study resulted in incisor degeneration (degeneration of enamel and loss of ameloblast layer). once daily oral administration of infigratinib in a 26-week rat study resulted in bone effects (decreased bone strength consistent with decreases in total bone mineral density in lumbar vertebral bodies). once daily oral administration of infigratinib in a 39-week dog study resulted in increased growth plate thickness and fractures associated with increased physeal thickness, focal mixed reaction, and bone loss. 8.5 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. 8.6 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 [ see dosage and administration ( 2.5 ) and clinical pharmacology ( 12.3 ) ]. 8.7 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 [ see dosage and administration ( 2.6 ), clinical pharmacology ( 12.3 ) ].

mg/kg/day (<0.1 times the human exposure at the clinical dose of 125 mg). fetal abnormalities (external, soft tissue, and skeletal) were increased at ≥1 mg/kg/day (<0.1 times the human exposure at the clinical dose of 125 mg). in the embryo-fetal portion of a rat fertility study, infigratinib decreased the mean number of embryos and increased nonviable embryos and post-implantation loss in females at 3 mg/kg/day. once daily oral administration of infigratinib at ≥0.3 mg/kg/day to pregnant rabbits resulted in maternal toxicity and a corresponding reduction in fetal body weights.

ics serum phosphate truseltiq increased serum phosphate levels due to fgfr inhibition. serum phosphate increased with increasing exposures across the dose range of 20 to 150 mg once daily (0.16 to 1.2 times the approved recommended dosage), with increased risk of hyperphosphatemia with higher exposure to truseltiq. 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. 12.3 pharmacokinetics the infigratinib pharmacokinetic parameters are presented following administration of the approved recommended dosage in cholangiocarcinoma patients, unless otherwise specified. the mean (coefficient of variation [%cv]) steady-state maximum plasma concentration (c max ) and area under the curve over a dosing interval (auc 0‑24h ) of infigratinib and active metabolites, bhs697 and cqm157, are presented in table 5 . table 5: mean (%cv) exposure of infigratinib and active metabolites infigratinib bhs697 cqm157 c max 282.5 ng/ml (54%) 42.1 ng/ml (65%) 15.7 ng/ml (92%) auc 0‑24h 3780 ng•h/ml (59%) 717 ng•h/ml (55%) 428 ng•h/ml (72%) infigratinib c max and auc increased more than proportionally across the dose range of 5 to 150 mg (0.04 to 1.2 times the approved recommended dose). steady state was achieved within 15 days and the mean accumulation ratio was 8- and 5-fold for c max and auc, respectively. absorption median (range) time to achieve peak infigratinib plasma concentration (t max ) was 6 hours (2 to 7 hours) at steady state. 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 auc inf of infigratinib increased by 80%-120% and c max increased by 60%-80%, the median t max 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 auc inf of infigratinib increased by 70%, c max increased by 90%, and the median t max 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. the major drug-related moiety in plasma was unchanged infigratinib (38% of dose) in a human [ 14 c] mass balance study, followed by two active metabolites, bhs697 and cqm157 (each at >10% of dose). bhs697 is mainly metabolized by cyp3a4 and cqm157 is metabolized through both phase i and phase ii biotransformation pathways. bhs697 and cqm157 contribute about 16% to 33% and 9% to 12% of overall pharmacologic activity, respectively. 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). 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). 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. 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 [ see use in specific populations ( 8.7 ) ]. drug interaction studies clinical studies strong cyp3a inhibitors : coadministration of multiple doses of itraconazole (strong cyp3a inhibitor) increased infigratinib auc 0-inf by 622% and c max by 164%, increased bhs697 auc 0-inf by 174%, and decreased cqm157 c max by 69%, respectively [ see drug interactions ( 7.1 ) ]. strong cyp3a inducers : coadministration of multiple doses of rifampin (strong cyp3a inducer) decreased infigratinib auc 0-inf by 56% and c max by 44%, decreased bhs697 auc 0-inf by 65% and c max by 27%, and decreased cqm157 auc 0-inf by 76% and c max by 50%, respectively [ see drug interactions ( 7.1 ) ]. gastric acid-lowering agents : coadministration of multiple doses of lansoprazole (proton pump inhibitor) decreased infigratinib auc 0-inf by 45% and c max by 49%, decreased bhs697 auc 0-inf by 32% and c max by 44%, and decreased cqm157 auc 0-inf by 72% and c max by 55%, respectively [ see drug interactions ( 7.1 ) ]. cyp3a4 substrates : no clinically significant differences in pharmacokinetics of midazolam (sensitive cyp3a4 substrate) were observed when co-administered with truseltiq [ see drug interactions ( 7.1 ) ]. in vitro studies cytochrome p450 enzymes : infigratinib does not induce cyp1a2, cyp2b6, cyp2c9, or cyp3a4. infigratinib, bhs697, and cqm157 do not inhibit major cyp450 isozymes at clinically relevant concentrations. transporter systems : infigratinib inhibits mate1 and bcrp. infigratinib has a low potential to inhibit p-gp, bsep, oct1, oct2 and mate-2k at clinically relevant concentrations. infigratinib is a substrate for p-gp and bcrp. the metabolites bhs697 and cqm157 have a low potential to inhibit oatp1b1, oatp1b3, p-gp, or bcrp at clinically relevant concentrations. the effect of these metabolites to inhibit mate or oct at clinically relevant concentrations is unknown.

eak infigratinib plasma concentration (t max ) was 6 hours (2 to 7 hours) at steady state. 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 auc inf of infigratinib increased by 80%-120% and c max increased by 60%-80%, the median t max 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 auc inf of infigratinib increased by 70%, c max increased by 90%, and the median t max 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. the major drug-related moiety in plasma was unchanged infigratinib (38% of dose) in a human [ 14 c] mass balance study, followed by two active metabolites, bhs697 and cqm157 (each at >10% of dose). bhs697 is mainly metabolized by cyp3a4 and cqm157 is metabolized through both phase i and phase ii biotransformation pathways. bhs697 and cqm157 contribute about 16% to 33% and 9% to 12% of overall pharmacologic activity, respectively. 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). 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). 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. 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 [ see use in specific populations ( 8.7 ) ]. drug interaction studies clinical studies strong cyp3a inhibitors : coadministration of multiple doses of itraconazole (strong cyp3a inhibitor) increased infigratinib auc 0-inf by 622% and c max by 164%, increased bhs697 auc 0-inf by 174%, and decreased cqm157 c max by 69%, respectively [ see drug interactions ( 7.1 ) ]. strong cyp3a inducers : coadministration of multiple doses of rifampin (strong cyp3a inducer) decreased infigratinib auc 0-inf by 56% and c max by 44%, decreased bhs697 auc 0-inf by 65% and c max by 27%, and decreased cqm157 auc 0-inf by 76% and c max by 50%, respectively [ see drug interactions ( 7.1 ) ]. gastric acid-lowering agents : coadministration of multiple doses of lansoprazole (proton pump inhibitor) decreased infigratinib auc 0-inf by 45% and c max by 49%, decreased bhs697 auc 0-inf by 32% and c max by 44%, and decreased cqm157 auc 0-inf by 72% and c max by 55%, respectively [ see drug interactions ( 7.1 ) ]. cyp3a4 substrates : no clinically significant differences in pharmacokinetics of midazolam (sensitive cyp3a4 substrate) were observed when co-administered with truseltiq [ see drug interactions ( 7.1 ) ]. in vitro studies cytochrome p450 enzymes : infigratinib does not induce cyp1a2, cyp2b6, cyp2c9, or cyp3a4. infigratinib, bhs697, and cqm157 do not inhibit major cyp450 isozymes at clinically relevant concentrations. transporter systems : infigratinib inhibits mate1 and bcrp. infigratinib has a low potential to inhibit p-gp, bsep, oct1, oct2 and mate-2k at clinically relevant concentrations. infigratinib is a substrate for p-gp and bcrp. the metabolites bhs697 and cqm157 have a low potential to inhibit oatp1b1, oatp1b3, p-gp, or bcrp at clinically relevant concentrations. the effect of these metabolites to inhibit mate or oct at clinically relevant concentrations is unknown.

(range: 23 to 81 years), 62% were female, 72% were white, 3.7% were black or african american, 10% were asian, and 99% had a baseline eastern cooperative oncology group (ecog) performance status of 0 (42%) or 1 (57%). the presence of fgfr2 fusions or other rearrangements was determined in 104 enrolled patients (96%) with next generation sequencing (ngs) testing. eighty-eight (81%) patients had in-frame fgfr2 fusions, and bicc1 the most commonly reported fusion partner (n=27, 25%). twenty (19%) patients had other fgfr2 rearrangements that may not be in-frame with the partner gene or the partner gene was not identifiable. ninety-nine percent of patients had metastatic (stage iv) disease at the time of study entry. all patients had received at least 1 prior line of systemic therapy, 32% had 2 prior lines of therapy, and 29% had 3 or more prior lines of therapy. ninety-nine percent of patients received prior gemcitabine-based therapy and most (88%) had progressed on their prior gemcitabine-based therapy. efficacy results are summarized in table 6 . the median time to response was 3.6 months (range 1.4 – 7.4 months). table 6: efficacy results in study cbgj398x2204 truseltiq n=108 efficacy parameter bicr assessment orr (95% ci) 23% (16, 32) complete response, n (%) 1 (1%) partial response, n (%) 24 (22%) median dor (months) (95% ci) 5.0 (3.7, 9.3) patients with dor ≥6 months, n (%) 8 (32%) patients with dor ≥12 months, n (%) 1 (4%) abbreviations: bicr= blinded independent central review; ci=confidence interval; dor=duration of response; orr=overall response rate. note: data are according to recist v1.1.

s), 62% were female, 72% were white, 3.7% were black or african american, 10% were asian, and 99% had a baseline eastern cooperative oncology group (ecog) performance status of 0 (42%) or 1 (57%). the presence of fgfr2 fusions or other rearrangements was determined in 104 enrolled patients (96%) with next generation sequencing (ngs) testing. eighty-eight (81%) patients had in-frame fgfr2 fusions, and bicc1 the most commonly reported fusion partner (n=27, 25%). twenty (19%) patients had other fgfr2 rearrangements that may not be in-frame with the partner gene or the partner gene was not identifiable. ninety-nine percent of patients had metastatic (stage iv) disease at the time of study entry. all patients had received at least 1 prior line of systemic therapy, 32% had 2 prior lines of therapy, and 29% had 3 or more prior lines of therapy. ninety-nine percent of patients received prior gemcitabine-based therapy and most (88%) had progressed on their prior gemcitabine-based therapy. efficacy results are summarized in table 6 . the median time to response was 3.6 months (range 1.4 – 7.4 months). table 6: efficacy results in study cbgj398x2204 truseltiq n=108 efficacy parameter bicr assessment orr (95% ci) 23% (16, 32) complete response, n (%) 1 (1%) partial response, n (%) 24 (22%) median dor (months) (95% ci) 5.0 (3.7, 9.3) patients with dor ≥6 months, n (%) 8 (32%) patients with dor ≥12 months, n (%) 1 (4%) abbreviations: bicr= blinded independent central review; ci=confidence interval; dor=duration of response; orr=overall response rate. note: data are according to recist v1.1.

ng a 21-day supply (21 capsules, 100 mg infigratinib per capsule and 21 capsules; 25 mg infigratinib per capsule). [ndc-72730-101-01]. store truseltiq at 20°c to 25°c (68°f to 77°f), with excursions permitted between 15°c and 30°c (59°f and 86°f).