, or direct bilirubin (>uln) or active liver or biliary tract disease, avoid coadministration of turalio with other products known to cause hepatotoxicity [see warnings and precautions (5.1) ] . 7.2 effect of other drugs or food on turalio table 7: effect of other drugs or food on turalio moderate or strong cyp3a inhibitors clinical impact concomitant use of a moderate or strong cyp3a inhibitor may increase pexidartinib concentrations [see clinical pharmacology (12.3) ], which may increase the incidence and severity of adverse reactions of turalio. management reduce turalio dosage if concomitant use of moderate or strong cyp3a inhibitors, including grapefruit or grapefruit juice, cannot be avoided [see dosage and administration (2.3) ]. strong cyp3a inducers clinical impact concomitant use of a strong cyp3a inducer decreases pexidartinib concentrations [see clinical pharmacology (12.3) ] , which may decrease the efficacy of turalio. management avoid concomitant use of strong cyp3a inducers, including st john's wort. ugt inhibitors clinical impact concomitant use of a ugt inhibitor increases pexidartinib concentrations [see clinical pharmacology (12.3) ], which may increase the incidence and severity of adverse reactions of turalio. management reduce turalio dosage if concomitant use of ugt inhibitors cannot be avoided [see dosage and administration (2.3) ]. acid-reducing agents clinical impact concomitant use of a ppi decreases pexidartinib concentrations [see clinical pharmacology (12.3) ], which may decrease the efficacy of turalio. management avoid concomitant use of ppis with turalio. as an alternative to ppis, use locally-acting antacids or h 2 -receptor antagonists [see dosage and administration (2.4) ] . high-fat meal clinical impact taking turalio with a high-fat meal increased pexidartinib concentrations [see clinical pharmacology (12.3) ] , which may increase the incidence and severity of turalio adverse reactions, including hepatotoxicity [see warnings and precautions (5.1 , 5.4) ]. management take turalio with a low-fat meal (approximately 11 to 14 grams of total fat) . avoid taking turalio with a high-fat meal (approximately 55 to 65 grams of total fat) [see dosage and administration (2.1) ] . 7.3 effect of turalio on other drugs table 8: effect of turalio on other drugs cyp3a substrates clinical impact turalio is a moderate cyp3a inducer. concomitant use of turalio decreases the concentration of cyp3a substrates [see clinical pharmacology (12.3) ] , which may reduce the efficacy of these substrates . management avoid coadministration of turalio with hormonal contraceptives [see warnings and precautions (5.3) , use in specific populations (8.3) ]. avoid concomitant use of turalio with other cyp3a substrates, where minimal concentration changes may lead to serious therapeutic failures. if concomitant use is unavoidable, increase the cyp3a substrate dosage in accordance with approved product labeling.

a liver transplant. the mechanism of cholestatic hepatotoxicity is unknown and its occurrence cannot be predicted. it is unknown whether liver injury occurs in the absence of increased transaminases. in enliven, 3 of 61 (5%) patients who received turalio developed signs of serious liver injury, defined as alt or ast ≥3 × uln with total bilirubin ≥2 × uln. in these patients, peak alt ranged from 6 to 9 × uln, peak total bilirubin ranged from 2.5 to 15 × uln, and alkaline phosphatase (alp) was ≥2 × uln. alt, ast and total bilirubin improved to <2 × uln in these patients 1 to 7 months after discontinuing turalio. avoid turalio in patients with pre-existing increased serum transaminases; total bilirubin or direct bilirubin (>uln); or active liver or biliary tract disease, including increased alp. monitor liver tests, including ast, alt, total bilirubin, direct bilirubin, alp and gamma-glutamyl transferase (ggt), prior to initiation of turalio, weekly for the first 8 weeks, every 2 weeks for the next month and every 3 months thereafter. withhold and dose reduce, or permanently discontinue turalio based on the severity of the hepatotoxicity [see dosage and administration (2.2) ] . rechallenge with a reduced dose of turalio may result in a recurrence of increased serum transaminases, bilirubin, or alp. monitor liver tests weekly for the first month after rechallenge. 5.2 turalio rems program turalio is only available through a restricted program under a rems, because of the risk of hepatotoxicity [see warnings and precautions (5.1) ] . notable requirements of the turalio rems program include the following: prescribers must be certified with the program by enrolling and completing training. patients must complete and sign an enrollment form for inclusion in a patient registry. pharmacies must be certified with the program and must only dispense to patients who are authorized to receive turalio. further information is available at www.turaliorems.com or 1-833-887-2546. 5.3 embryo-fetal toxicity based on animal studies and its mechanism of action, turalio may cause fetal harm when administered to a pregnant woman. oral administration of pexidartinib to pregnant rats and rabbits during the period of organogenesis resulted in malformations, increased post-implantation loss, and abortion at exposures approximately equal to the human exposure at the recommended dose based on area under the curve (auc). advise pregnant women of the potential risk to a fetus. advise females of reproductive potential to use effective non-hormonal contraception, since turalio can render hormonal contraceptives ineffective, during treatment with turalio and for 1 month after the final dose. advise males with female partners of reproductive potential to use effective contraception during treatment with turalio and for 1 week after the final dose [see drug interactions (7.3) , use in specific populations (8.1 , 8.3) ] . 5.4 potential risks associated with a high-fat meal taking turalio with a high-fat meal increases pexidartinib concentrations, which may increase the incidence and severity of adverse reactions, including hepatotoxicity [see clinical pharmacology (12.2 , 12.3) ]. instruct patients to take turalio with a low-fat meal (approximately 11 to 14 grams of total fat) and to avoid taking turalio with a high-fat meal (approximately 55 to 65 grams of total fat). consider referring patients to a dietician as deemed necessary [see dosage and administration (2.1) , warnings and precautions (5.1) , drug interactions (7.2) ].

dose at its scheduled time. 2.2 dosage modifications for adverse reactions the recommended dose reductions for adverse reactions are provided in table 1. table 1: recommended dose reductions for turalio for adverse reactions dose reduction total daily dose administration of total daily dose with low-fat meal first 375 mg 125 mg in the morning and 250 mg in the evening second 250 mg 125 mg twice daily permanently discontinue turalio in patients who are unable to tolerate 125 mg orally twice daily. the recommended dosage modifications for adverse reactions are summarized in table 2. table 2: recommended dosage modifications for turalio for adverse reactions adverse reaction severity turalio dosage modifications alt = alanine aminotransferase; alp = alkaline phosphatase; ast = aspartate aminotransferase; db = direct bilirubin; ggt = gamma-glutamyl transferase; tb = total bilirubin; uln = upper limit of normal hepatotoxicity [see warnings and precautions (5.1) ] increased alt and/or ast greater than 3 to 5 times uln withhold and monitor liver tests weekly . if ast and alt are less than or equal to 3 times uln within 4 weeks, resume at reduced dose. if ast or alt is not less than or equal to 3 times uln in 4 weeks, permanently discontinue turalio. greater than 5 to 10 times uln withhold and monitor liver tests twice weekly . if ast and alt are less than or equal to 3 times uln within 4 weeks, resume at reduced dose. if ast or alt is not less than or equal to 3 times uln in 4 weeks, permanently discontinue turalio. greater than 10 times uln permanently discontinue turalio. monitor liver tests twice weekly until ast or alt is less than or equal to 5 times uln, then weekly until less than or equal to 3 times uln. increased alp confirm alp elevations as liver isozyme fraction. and ggt alp greater than 2 times uln with ggt greater than 2 times uln permanently discontinue turalio. monitor liver tests twice weekly until alp is less than or equal to 5 times uln, then weekly until less than or equal to 2 times uln. increased bilirubin tb greater than uln to less than 2 times uln or db greater than uln and less than 1.5 times uln withhold and monitor liver tests twice weekly . if an alternate cause for increased bilirubin is confirmed and bilirubin is less than uln within 4 weeks, resume at reduced dose. if bilirubin is not less than uln in 4 weeks, permanently discontinue turalio. tb greater or equal to 2 times uln or db greater than 1.5 times uln permanently discontinue turalio. monitor liver tests twice weekly until bilirubin is less than or equal to uln. adverse reactions or other laboratory abnormalities [see adverse reactions (6.1) ] any severe or intolerable withhold until improvement or resolution. resume at a reduced dose upon improvement or resolution. 2.3 concomitant use of moderate or strong cyp3a inhibitors or ugt inhibitors avoid concomitant use of turalio with moderate or strong cyp3a inhibitors or ugt inhibitors during treatment with turalio. if concomitant use with a moderate or strong cyp3a inhibitor or ugt inhibitor cannot be avoided, reduce the turalio dose according to the recommendations in table 3. if concomitant use of a moderate or strong cyp3a inhibitor or ugt inhibitor is discontinued, increase the turalio dose (after 3 plasma half-lives of the moderate or strong cyp3a inhibitor or ugt inhibitor) to the dose that was used before starting the inhibitor [see clinical pharmacology (12.3) ] . table 3: recommended dosage reductions for turalio for concomitant use of moderate or strong cyp3a inhibitors or ugt inhibitors total daily dose the total daily dose represents the recommended dose (row one) and the recommended dose after modifications due to adverse reactions, renal impairment, or moderate hepatic impairment (rows two and three) [see dosage and administration (2.2 , 2.5 , 2.6) ]. modified total daily dose for concomitant use with moderate or strong cyp3a inhibitors or ugt inhibitors dosing schedule for modified total daily dose for use with moderate or strong cyp3a inhibitors or ugt inhibitors administer with low-fat meal 500 mg 250 mg 125 mg twice daily 375 mg 250 mg 125 mg twice daily 250 mg 125 mg 125 mg once daily 2.4 concomitant use of acid-reducing agents avoid the concomitant use of proton pump inhibitors (ppi) while taking turalio. as an alternative to a ppi, administer turalio 2 hours before or 2 hours after taking a locally-acting antacid, or if using a histamine 2 (h 2 )-receptor antagonist, administer turalio at least 2 hours before or 10 hours after taking an h 2 -receptor antagonist [see clinical pharmacology (12.3) ] . 2.5 dosage modification for renal impairment the recommended dosage of turalio for patients with mild to severe renal impairment (creatinine clearance [clcr] 15 to 89 ml/min estimated by cockcroft-gault using actual body weight) is 125 mg in the morning and 250 mg in the evening with a low-fat meal [see clinical pharmacology (12.3) ] . 2.6 dosage modification for hepatic impairment the recommended dosage of turalio for patients with moderate hepatic impairment (total bilirubin >1.5 to 3 × upper limit of normal (uln), not due to gilbert's syndrome, with any ast) is 125 mg twice daily with a low-fat meal [see clinical pharmacology (12.3) ] . turalio has not been studied in patients with severe hepatic impairment (total bilirubin >3 to 10 × uln and any ast).

wice daily administered with a low-fat meal has been established based on adequate and well-controlled studies of turalio 400 mg orally twice daily administered on an empty stomach and additional pharmacokinetic data that indicate there is no clinically significant difference in the relative exposure between the two dosages [see clinical pharmacology (12.3) ]. the safety of turalio was evaluated in enliven [see clinical studies (14.1) ] . enliven excluded patients with alt, ast, or total bilirubin >1.5 × uln; and known active or chronic infection with hepatitis b or c virus, or human immunodeficiency virus. patients received turalio without food at a dose of 400 mg in the morning and 600 mg in the evening orally for 2 weeks followed by 400 mg orally twice daily until disease progression or unacceptable toxicity . seventy-nine percent of patients received turalio for 6 months or longer and 66% for greater than one year. the median age of turalio-treated patients was 44 years (range: 22-75), 57% were females, and 85% were white. serious adverse reactions were reported in 13% of patients who received turalio. most frequent (occurring in >1 patient) serious adverse reactions included abnormal liver tests (3.3%) and hepatotoxicity (3.3%). permanent discontinuation due to an adverse reaction occurred in 13% of patients who received turalio. most frequent adverse reactions (occurring in >1 patient) requiring permanent discontinuation included increased alt (4.9%), increased ast (4.9%) and hepatotoxicity (3.3%). dose reductions or interruptions occurred in 38% of patients who received turalio. most frequent adverse reactions (occurring in >1 patient) requiring a dosage reduction or interruption were increased alt (13%), increased ast (13%), nausea (8%), increased alp (7%), vomiting (4.9%), increased bilirubin (3.3%), increased ggt (3.3%), dizziness (3.3%), and abdominal pain (3.3%). the most common (>20%) adverse reactions, including laboratory abnormalities, in patients who received turalio were: increased lactate dehydrogenase (ldh), increased ast, hair color changes, fatigue, increased alt, decreased neutrophils, increased cholesterol, increased alp, decreased lymphocytes, eye edema, decreased hemoglobin, rash, dysgeusia and decreased phosphate. tables 4, 5 and 6 summarize the adverse reactions and laboratory abnormalities in enliven during the randomized phase (week 25). table 4: adverse reactions (≥10% all grades or >2% grade ≥ 3) in patients receiving turalio with a difference between arms of >5% compared to placebo through week 25 in enliven turalio n=61 placebo n=59 adverse reaction all grades (%) grade ≥ 3 (%) all grades (%) grade ≥ 3 (%) skin and subcutaneous tissue hair color changes 67 0 3.4 0 rash rash includes rash, maculo-papular rash, rash pruritic, urticaria, erythema, dermatitis acneiform, dermatitis allergic. 28 1.6 7 0 pruritus pruritis includes pruritus, pruritus generalized. 18 0 3.4 0 general fatigue fatigue includes fatigue, asthenia, malaise. 64 0 41 0 peripheral edema peripheral edema includes face edema, localized edema, edema peripheral, peripheral swelling. 20 0 7 0 eye eye edema eye edema includes periorbital edema, eye edema, eyelid edema, papilledema. 30 1.6 5 0 nervous system dysgeusia dysgeusia includes dysgeusia, ageusia. 26 0 1.7 0 neuropathy neuropathy includes neuropathy peripheral, paresthesia, hypoesthesia, burning sensation. 10 0 5 0 gastrointestinal vomiting 20 1.6 5 0 constipation 12 0 5 0 metabolism and nutrition decreased appetite 16 0 10 0 vascular hypertension 15 4.9 10 0 table 5: hepatic laboratory abnormalities (≥10% all grades or >2% grade ≥ 3) worsening from baseline in patients receiving turalio with a difference between arms of >5% compared to placebo through week 25 in enliven turalio each test incidence is based on the number of patients who had both a baseline and at least one on-study measurement turalio (n=61) and placebo (n=59). placebo laboratory abnormality graded per nci ctcae v 4.03 grade 1 (%) grade 2 (%) grade ≥ 3 (%) grade 1 (%) grade 2 (%) grade ≥ 3 (%) alt = alanine aminotransferase; ast = aspartate aminotransferase; alp = alkaline phosphatase liver tests increased ast 61 15 12 15 0 0 increased alt 31 13 20 22 0 0 increased alp 31 3.3 4.9 1.7 0 0 increased bilirubin 3.3 3.3 3.3 0 0 0 table 6: other laboratory abnormalities worsening from baseline (≥10% all grades or >2% of grade ≥ 3) in patients receiving turalio with a difference between arms of >5% compared to placebo through week 25 in enliven turalio each test incidence is based on the number of patients who had both a baseline and at least one on-study measurement turalio (n = 61) and placebo (n = 58-59). placebo laboratory abnormality graded per nci ctcae v 4.03 except for ldh all grades (%) grade ≥3 (%) all grades (%) grade ≥3 (%) ldh=lactate dehydrogenase chemistry increased ldh ldh: grade 1 >uln to ≤2.5 × uln; grade 2 >2.5 to ≤5 × uln; grade 3 >5 to ≤20 × uln; grade 4 >20 × uln 92 0 5 0 increased cholesterol 44 4.9 25 0 decreased phosphate 25 3.3 5 0 hematology decreased neutrophils 44 3.3 9 0 decreased lymphocytes 38 1.6 3.4 0 decreased hemoglobin 30 0 14 1.7 decreased platelets 15 0 5 0 clinically relevant adverse reactions occurring in <10% of patients were: eye: blurred vision, photophobia, diplopia, reduced visual acuity gastrointestinal: dry mouth, stomatitis, mouth ulceration general: pyrexia hepatobiliary: cholangitis, hepatotoxicity, liver disorder neurological: cognitive disorders (memory impairment, amnesia, confusional state, disturbance in attention, attention deficit/hyperactivity disorder) skin and subcutaneous tissue: alopecia, skin pigment changes (hypopigmentation, depigmentation, discoloration, hyperpigmentation) 6.2 postmarketing experience the following adverse reactions have been identified during post-approval use of turalio. because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. investigations: blood creatine phosphokinase increased

, or direct bilirubin (>uln) or active liver or biliary tract disease, avoid coadministration of turalio with other products known to cause hepatotoxicity [see warnings and precautions (5.1) ] . 7.2 effect of other drugs or food on turalio table 7: effect of other drugs or food on turalio moderate or strong cyp3a inhibitors clinical impact concomitant use of a moderate or strong cyp3a inhibitor may increase pexidartinib concentrations [see clinical pharmacology (12.3) ], which may increase the incidence and severity of adverse reactions of turalio. management reduce turalio dosage if concomitant use of moderate or strong cyp3a inhibitors, including grapefruit or grapefruit juice, cannot be avoided [see dosage and administration (2.3) ]. strong cyp3a inducers clinical impact concomitant use of a strong cyp3a inducer decreases pexidartinib concentrations [see clinical pharmacology (12.3) ] , which may decrease the efficacy of turalio. management avoid concomitant use of strong cyp3a inducers, including st john's wort. ugt inhibitors clinical impact concomitant use of a ugt inhibitor increases pexidartinib concentrations [see clinical pharmacology (12.3) ], which may increase the incidence and severity of adverse reactions of turalio. management reduce turalio dosage if concomitant use of ugt inhibitors cannot be avoided [see dosage and administration (2.3) ]. acid-reducing agents clinical impact concomitant use of a ppi decreases pexidartinib concentrations [see clinical pharmacology (12.3) ], which may decrease the efficacy of turalio. management avoid concomitant use of ppis with turalio. as an alternative to ppis, use locally-acting antacids or h 2 -receptor antagonists [see dosage and administration (2.4) ] . high-fat meal clinical impact taking turalio with a high-fat meal increased pexidartinib concentrations [see clinical pharmacology (12.3) ] , which may increase the incidence and severity of turalio adverse reactions, including hepatotoxicity [see warnings and precautions (5.1 , 5.4) ]. management take turalio with a low-fat meal (approximately 11 to 14 grams of total fat) . avoid taking turalio with a high-fat meal (approximately 55 to 65 grams of total fat) [see dosage and administration (2.1) ] . 7.3 effect of turalio on other drugs table 8: effect of turalio on other drugs cyp3a substrates clinical impact turalio is a moderate cyp3a inducer. concomitant use of turalio decreases the concentration of cyp3a substrates [see clinical pharmacology (12.3) ] , which may reduce the efficacy of these substrates . management avoid coadministration of turalio with hormonal contraceptives [see warnings and precautions (5.3) , use in specific populations (8.3) ]. avoid concomitant use of turalio with other cyp3a substrates, where minimal concentration changes may lead to serious therapeutic failures. if concomitant use is unavoidable, increase the cyp3a substrate dosage in accordance with approved product labeling.

isk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. data animal data embryo-fetal development studies investigating the administration of pexidartinib during the period of organogenesis were conducted in rats and rabbits. in rats, pexidartinib resulted in increased post-implantation loss and fetal malformations including localized fetal edema, absence of kidney and ureter, abnormalities of the reproductive tract, and developmental variations including misshapen kidney, decreased skeletal ossification and higher mean litter proportions of slightly or moderately malaligned sternebrae at doses of 40 mg/kg (approximately equal to the human exposure at the recommended dose). in rabbits, administration of pexidartinib resulted in increased post-implantation loss, abortion, and fetal malformations including absence of kidney or ureter, rudimentary, misshapen or malpositioned kidney, rib abnormalities, and skeletal variations of accessory skull bones at doses of 60 mg/kg (approximately equal to the human exposure at the recommended dose). 8.2 lactation risk summary there are no data on the presence of pexidartinib or its metabolites in either human or animal 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 turalio and for at least 1 week after the final dose. 8.3 females and males of reproductive potential turalio may cause fetal harm when administered to a pregnant woman [see use in specific populations (8.1) ] . pregnancy testing verify pregnancy status in females of reproductive potential prior to the initiation of turalio [see use in specific populations (8.1) ] . contraception females advise females of reproductive potential to use effective non-hormonal contraception during treatment with turalio and for 1 month after the final dose. counsel patients to use non-hormonal method(s) of contraception, since turalio can render hormonal contraceptives ineffective [see drug interactions (7.3) , nonclinical toxicology (13.1) ] . males advise male patients with female partners of reproductive potential to use effective contraception during treatment with turalio and for 1 week after the final dose [see nonclinical toxicology (13.1) ] . infertility based on findings from animal studies, turalio may impair both male and female fertility [see nonclinical toxicology (13.1) ]. 8.4 pediatric use the safety and effectiveness of turalio in pediatric patients have not been established. 8.5 geriatric use clinical studies of turalio did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 8.6 renal impairment reduce the dosage when administering turalio to patients with mild to severe renal impairment (clcr 15 to 89 ml/min, estimated by cockcroft-gault [c-g]) [see dosage and administration (2.5) , clinical pharmacology (12.3) ] . 8.7 hepatic impairment no dosage adjustment is recommended for patients with mild hepatic impairment (total bilirubin ≤ upper limit of normal [uln] with ast > uln or total bilirubin >1 to 1.5 × uln with any ast) [see clinical pharmacology (12.3) ] . reduce the dosage of turalio for patients with moderate hepatic impairment (total bilirubin >1.5 to 3 × uln, not due to gilbert's syndrome, with any ast) [see dosage and administration (2.6) , clinical pharmacology (12.3) ] . turalio has not been studied in patients with severe hepatic impairment (total bilirubin >3 to 10 × uln and any ast).

nd rabbits. in rats, pexidartinib resulted in increased post-implantation loss and fetal malformations including localized fetal edema, absence of kidney and ureter, abnormalities of the reproductive tract, and developmental variations including misshapen kidney, decreased skeletal ossification and higher mean litter proportions of slightly or moderately malaligned sternebrae at doses of 40 mg/kg (approximately equal to the human exposure at the recommended dose). in rabbits, administration of pexidartinib resulted in increased post-implantation loss, abortion, and fetal malformations including absence of kidney or ureter, rudimentary, misshapen or malpositioned kidney, rib abnormalities, and skeletal variations of accessory skull bones at doses of 60 mg/kg (approximately equal to the human exposure at the recommended dose).

er day administered on an empty stomach (0.25 to 1.5 times the exposure from the recommended dose). cardiac electrophysiology at two times the mean maximum exposure of the recommended dosage, turalio does not prolong the qtc interval to any clinically relevant extent. 12.3 pharmacokinetics the pharmacokinetics of turalio was evaluated following single doses in healthy subjects and following multiple doses in patients as summarized in table 9. table 9: turalio exposure and pharmacokinetic parameters general information steady state exposure [mean (sd)] pexidartinib 400 mg twice daily on an empty stomach (similar exposure to that of the recommended dosage) c max 8625 (2746) ng/ml auc 0-12h 77465 (24975) ng∙h/ml dose proportionality pexidartinib exposure (c max and auc 0-inf ) increased linearly over the single oral dose range of 200 to 2400 mg administered on an empty stomach (0.5 to 6 times the exposure from the recommended dose). time to steady state estimated based on half life approximately 7 days accumulation ratio (auc) [median] 3.6 absorption t max [median] 2.5 hours effect of food turalio 400 mg with a high-fat meal the high-fat meal comprised 800 to 1000 calories with approximately 50% from fat (approximately 55 to 65 grams of total fat). compared to an empty stomach: increased pexidartinib c max and auc 0-inf by 100% delayed t max by 2.5 hours turalio 400 mg with a low-fat meal the low-fat meal comprised approximately 400 calories with 25% from fat (approximately 11 to 14 grams of total fat). compared to an empty stomach: increased pexidartinib c max by 56% and auc 0-inf by 59% delayed t max by 1.5 hours predicted relative auc 0-24h of turalio 250 mg with a low-fat meal to that of turalio 400 mg on an empty stomach no clinically significant difference distribution in vitro plasma protein binding greater than 99% human serum albumin: 99.9% α-1 acid glycoprotein: 89.9% apparent volume of distribution (vz/f) [mean (cv%)] after a single oral dose of pexidartinib 187 l (27%) elimination apparent clearance [mean (cv%)] 5.1 l/h (36%) t 1/2 [mean (sd)] 26.6 (6.5) hours metabolism primary pathway oxidation: cyp3a4 glucuronidation: ugt1a4 n -glucuronide metabolite major inactive metabolite formed by ugt1a4 approximately 10% higher exposure than pexidartinib after a single dose excretion after a single oral dose of radiolabeled pexidartinib feces: 65% (44% as unchanged) urine: 27% as metabolites (≥10% as n -glucuronide) specific populations no clinically meaningful differences in the pharmacokinetics of pexidartinib were observed based on age (18 to 84 years), sex, race (white and black), or mild hepatic impairment (total bilirubin ≤ uln with ast > uln or total bilirubin > 1 to 1.5 × uln with any ast). patients with renal impairment mild (clcr 60 to 89 ml/min), moderate (clcr 30 to 59 ml/min) and severe (clcr 15 to 29 ml/min) renal impairment increased pexidartinib exposure (auc) by approximately 30%, relative to that in patients with normal renal function (clcr ≥90 ml/min). patients with hepatic impairment moderate hepatic impairment (total bilirubin > 1.5 to 3 × uln, not due to gilbert's syndrome, with any ast) increased pexidartinib exposure (auc) by 43% relative to exposure in patients with normal hepatic function (total bilirubin and ast ≤ uln). the pharmacokinetics of pexidartinib have not been studied in patients with severe hepatic impairment (total bilirubin > 3 to 10 × uln with any ast). drug interaction studies clinical studies effects of other drugs on pexidartinib strong or moderate cyp3a inducers: coadministration of rifampicin (strong cyp3a inducer) decreased pexidartinib c max by 33% and auc 0-inf by 65%. coadministration of efavirenz (moderate cyp3a inducer) is predicted to have no clinically significant differences in pexidartinib pharmacokinetics. strong or moderate cyp3a inhibitors: coadministration of itraconazole (strong cyp3a inhibitor) increased pexidartinib c max by 48% and auc 0-inf by 70%. coadministration of fluconazole (moderate cyp3a inhibitor) is predicted to increase pexidartinib c max by 41% and auc by 67% at steady state. ugt inhibitors: coadministration of probenecid (ugt inhibitor) increased pexidartinib auc 0-inf by 60% with no effect on c max . acid-reducing agents: coadministration of esomeprazole (proton pump inhibitor) decreased pexidartinib c max by 55% and auc 0-inf by 50%. the effects of h 2 -receptor antagonists and locally-acting antacids on pexidartinib pharmacokinetics have not been studied. effects of pexidartinib on other drugs cyp3a substrates: coadministration of turalio at the approved recommended dosage decreased midazolam (cyp3a substrate) c max by 28% and auc 0-inf by 59%. other drugs: when coadministered with omeprazole (cyp2c19 substrate), tolbutamide (cyp2c9 substrate), digoxin (p-gp substrate), or cyp2c8 substrate with turalio, no clinically significant differences in their pharmacokinetics were observed or predicted. in vitro studies cyp/ugt enzymes: pexidartinib inhibited and induced cyp2b6 at clinically relevant concentrations . pexidartinib inhibited ugt1a1 at clinically relevant concentrations. transporters: pexidartinib is not a substrate for p-gp, bcrp, oat1, oat3, oct1, oct2, oatp1b1, oatp1b3, oatp2b1, and bsep. pexidartinib is an inhibitor of mate1, mate2-k, oatp1b1, oatp1b3 and oatp2b1.

. compared to an empty stomach: increased pexidartinib c max and auc 0-inf by 100% delayed t max by 2.5 hours turalio 400 mg with a low-fat meal the low-fat meal comprised approximately 400 calories with 25% from fat (approximately 11 to 14 grams of total fat). compared to an empty stomach: increased pexidartinib c max by 56% and auc 0-inf by 59% delayed t max by 1.5 hours predicted relative auc 0-24h of turalio 250 mg with a low-fat meal to that of turalio 400 mg on an empty stomach no clinically significant difference distribution in vitro plasma protein binding greater than 99% human serum albumin: 99.9% α-1 acid glycoprotein: 89.9% apparent volume of distribution (vz/f) [mean (cv%)] after a single oral dose of pexidartinib 187 l (27%) elimination apparent clearance [mean (cv%)] 5.1 l/h (36%) t 1/2 [mean (sd)] 26.6 (6.5) hours metabolism primary pathway oxidation: cyp3a4 glucuronidation: ugt1a4 n -glucuronide metabolite major inactive metabolite formed by ugt1a4 approximately 10% higher exposure than pexidartinib after a single dose excretion after a single oral dose of radiolabeled pexidartinib feces: 65% (44% as unchanged) urine: 27% as metabolites (≥10% as n -glucuronide) specific populations no clinically meaningful differences in the pharmacokinetics of pexidartinib were observed based on age (18 to 84 years), sex, race (white and black), or mild hepatic impairment (total bilirubin ≤ uln with ast > uln or total bilirubin > 1 to 1.5 × uln with any ast). patients with renal impairment mild (clcr 60 to 89 ml/min), moderate (clcr 30 to 59 ml/min) and severe (clcr 15 to 29 ml/min) renal impairment increased pexidartinib exposure (auc) by approximately 30%, relative to that in patients with normal renal function (clcr ≥90 ml/min). patients with hepatic impairment moderate hepatic impairment (total bilirubin > 1.5 to 3 × uln, not due to gilbert's syndrome, with any ast) increased pexidartinib exposure (auc) by 43% relative to exposure in patients with normal hepatic function (total bilirubin and ast ≤ uln). the pharmacokinetics of pexidartinib have not been studied in patients with severe hepatic impairment (total bilirubin > 3 to 10 × uln with any ast). drug interaction studies clinical studies effects of other drugs on pexidartinib strong or moderate cyp3a inducers: coadministration of rifampicin (strong cyp3a inducer) decreased pexidartinib c max by 33% and auc 0-inf by 65%. coadministration of efavirenz (moderate cyp3a inducer) is predicted to have no clinically significant differences in pexidartinib pharmacokinetics. strong or moderate cyp3a inhibitors: coadministration of itraconazole (strong cyp3a inhibitor) increased pexidartinib c max by 48% and auc 0-inf by 70%. coadministration of fluconazole (moderate cyp3a inhibitor) is predicted to increase pexidartinib c max by 41% and auc by 67% at steady state. ugt inhibitors: coadministration of probenecid (ugt inhibitor) increased pexidartinib auc 0-inf by 60% with no effect on c max . acid-reducing agents: coadministration of esomeprazole (proton pump inhibitor) decreased pexidartinib c max by 55% and auc 0-inf by 50%. the effects of h 2 -receptor antagonists and locally-acting antacids on pexidartinib pharmacokinetics have not been studied. effects of pexidartinib on other drugs cyp3a substrates: coadministration of turalio at the approved recommended dosage decreased midazolam (cyp3a substrate) c max by 28% and auc 0-inf by 59%. other drugs: when coadministered with omeprazole (cyp2c19 substrate), tolbutamide (cyp2c9 substrate), digoxin (p-gp substrate), or cyp2c8 substrate with turalio, no clinically significant differences in their pharmacokinetics were observed or predicted. in vitro studies cyp/ugt enzymes: pexidartinib inhibited and induced cyp2b6 at clinically relevant concentrations . pexidartinib inhibited ugt1a1 at clinically relevant concentrations. transporters: pexidartinib is not a substrate for p-gp, bcrp, oat1, oat3, oct1, oct2, oatp1b1, oatp1b3, oatp2b1, and bsep. pexidartinib is an inhibitor of mate1, mate2-k, oatp1b1, oatp1b3 and oatp2b1.

rse effects on sperm concentration, production, motility, and morphology. lower testicular and epididymal weights occurred in this study at doses of ≥10 mg/kg/day (approximately 0.3 times the human exposure at the recommended dose). this is consistent with findings in chronic toxicology studies of germ cell depletion of the testes and hypospermia and cellular debris in the epididymis in male reproductive tissues of both rats and dogs at respective doses as low as 20 and 30 mg/kg/day (approximately 0.6 and 0.1 times the human exposure at the recommended dose). in rats, these changes persisted following a 16-week recovery period at the 60 mg/kg/day dose level (approximately 1.5 times the human exposure at the recommended dose). in female rats, necrosis of corpora lutea occurred at doses ≥0.5 mg/kg/day (approximately 0.01 times the human exposure at the recommended dose) with pigment deposition within the interstitium of the ovaries, an increased incidence of luteal cysts and incidence/severity of hemorrhage of corpora lutea, and a decreased incidence of retained antral follicles and decreased corpora lutea at 60 mg/kg (approximately 1.8 times the human exposure at the recommended dose). in female dogs there were decreased follicle numbers and moderate atrophy of the oviduct, uterus, and cervix at doses as low as 1 mg/kg (approximately 0.01 times the human exposure at the recommended dose). 13.2 animal toxicology and/or pharmacology in repeat dose toxicity studies of up to 26 weeks in rats, there were findings of myxomatous change in the skin, tongue, and gastrointestinal tract, lymphoid depletion of the bone marrow and thymus, and chronic progressive nephropathy of the kidney at 20 mg/kg/day (approximately 0.6 times the human exposure at the recommended dose). similar changes occurred in the rat carcinogenicity study along with alterations in the tunica intima of the aorta. vascular inflammation consistent with polyarteritis nodosa occurred in male rats at 60 mg/kg/day (approximately 1.5 times the human exposure at the recommended dose). there were also dose-dependent findings of minimal to moderate subphyseal or cortical hyperostosis and physeal hypertrophy in the femur that correlated with decreased systemic phosphate levels at doses ≥ 60 mg/kg.

ntration, production, motility, and morphology. lower testicular and epididymal weights occurred in this study at doses of ≥10 mg/kg/day (approximately 0.3 times the human exposure at the recommended dose). this is consistent with findings in chronic toxicology studies of germ cell depletion of the testes and hypospermia and cellular debris in the epididymis in male reproductive tissues of both rats and dogs at respective doses as low as 20 and 30 mg/kg/day (approximately 0.6 and 0.1 times the human exposure at the recommended dose). in rats, these changes persisted following a 16-week recovery period at the 60 mg/kg/day dose level (approximately 1.5 times the human exposure at the recommended dose). in female rats, necrosis of corpora lutea occurred at doses ≥0.5 mg/kg/day (approximately 0.01 times the human exposure at the recommended dose) with pigment deposition within the interstitium of the ovaries, an increased incidence of luteal cysts and incidence/severity of hemorrhage of corpora lutea, and a decreased incidence of retained antral follicles and decreased corpora lutea at 60 mg/kg (approximately 1.8 times the human exposure at the recommended dose). in female dogs there were decreased follicle numbers and moderate atrophy of the oviduct, uterus, and cervix at doses as low as 1 mg/kg (approximately 0.01 times the human exposure at the recommended dose).

istered on an empty stomach: 400 mg in the morning and 600 mg in the evening for 2 weeks followed by 400 mg twice daily until unacceptable toxicity or disease progression. randomization was stratified by geographic region (us vs. non-us countries) and disease location (upper extremity vs. lower extremity involvement). patients who completed treatment in the double-blind, randomized part of the trial were eligible to advance to an open-label extension part in which all patients were given the option to receive pexidartinib. the major efficacy outcome measure was overall response rate (orr) as assessed by blinded independent central review (bicr) at week 25 using recist v1.1. additional efficacy outcome measures were mean change from baseline in range of motion of the affected joint at week 25 and orr as assessed by bicr at week 25 using tumor volume score (tvs). range of motion was measured as a percent of normal reference range for the affected joint. range of motion assessments were performed by a third-party clinical assessor using a goniometer. tvs was defined in enliven as the estimated volume of the maximally distended synovial cavity or tendon sheath involved, measured in 10% increments. patients in the placebo arm were offered turalio at week 25 beginning with a 400 mg twice daily dose, as permitted by the study protocol. a total of 120 patients were randomized, 61 to the turalio arm and 59 to the placebo arm. the median age was 44 years (range: 18-79); 59% were females; 88% were white; 53% had prior surgery; 88% were diagnosed with diffuse tgct; and 9% had previously been treated with systemic therapy. disease locations were knee (61%), ankle (18%), hip (11%), wrist (3%), foot (3%) and other (5%). enliven demonstrated a statistically significant improvement in orr in patients randomized to turalio compared with placebo. efficacy results are summarized in table 10. table 10: efficacy results assessed at week 25 for enliven efficacy parameter turalio n=61 placebo n=59 ci: confidence interval; na: not applicable; sd: standard deviation; ls: least squares; +: denotes ongoing at last assessment overall response rate (orr) blinded independent central review , data cut-off date january 31, 2018 orr (95% ci) 38% (27%, 50%) 0 (0, 6%) complete response 15% 0 partial response 23% 0 p-value fisher's exact test <0.0001 duration of response (dor) range (months) 6.9+, 24.9+ na the analysis of mean change from baseline in range of motion at week 25 demonstrated a statistically significant improvement in patients randomized to turalio compared to placebo. figure 1 shows the change from baseline in range of motion for each patient at week 25 (turalio n=45, placebo n=43). results were excluded for 1 patient with missing baseline and 31 patients with a missing range of motion assessment at week 25. figure 1: change from baseline in range of motion at week 25 for enliven orr by tvs was 56% (95% ci: 43%, 67%) in patients randomized to the turalio arm and 0% in patients randomized to the placebo arm; p < 0.0001. at completion of the open-label extension part of the study in which all patients received turalio, the orr using recist v1.1 was 61% (95% ci: 48%, 72%) in the 61 patients originally randomized to the turalio arm. the median duration of response was not reached (range: 4.6+, 63.4+ months) in the 37 responders. figure 1

n or suspected pregnancy [see warnings and precautions (5.3) , use in specific populations (8.1 , 8.3) ] . advise females of reproductive potential to use effective non-hormonal contraception during treatment with turalio and for 1 month after the final dose [see drug interactions (7.3) , use in specific populations (8.3) ] . advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 1 week after the final dose [see use in specific populations (8.3) , nonclinical toxicology (13.1) ] . lactation advise females not to breastfeed during treatment with turalio and for 1 week after the final dose [see use in specific populations (8.2) ]. infertility advise females and males of reproductive potential that turalio may impair fertility [see use in specific populations (8.3) , nonclinical toxicology (13.1) ]. administration instruct patients to take turalio with a low-fat meal (approximately 11 to 14 grams of total fat) and to avoid taking turalio with a high-fat meal (approximately 55 to 65 grams of total fat). consider referring patients to a dietician as deemed necessary [see dosage and administration (2.1) , warnings and precautions (5.4) , drug interactions (7.2) ] . instruct patients to swallow capsules whole (do not open, break, or chew) [see dosage and administration (2.1) ]. drug interactions advise patients to inform their healthcare providers of all concomitant products, including over-the-counter products and supplements [see dosage and administration (2) , drug interactions (7) ] .