Turalio

1 INDICATIONS AND USAGE TURALIO is indicated for the treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and not amenable to improvement with surgery. TURALIO is a kinase inhibitor indicated for the treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and not amenable to improvement with surgery.

Recommended Dosage : 250 mg orally twice daily with a low-fat meal (approximately 11 to 14 grams of total fat). See full prescribing information for dosage modifications due to adverse reactions, renal impairment and hepatic impairment. ( 2.2 , 2.5 , 2.6 )

2.1Recommended Dosage The

recommended dosage of TURALIO is 250 mg taken orally twice daily with a low-fat meal (approximately 11 to 14 grams of total fat) until disease progression or unacceptable toxicity . Taking TURALIO with a high-fat meal (approximately 55 to 65 grams of total fat) increases pexidartinib concentrations and may increase the risk of adverse reactions, including hepatotoxicity . Swallow TURALIO capsules whole. Do not open, break, or chew the capsules. If a patient vomits or misses a dose of TURALIO, instruct the patient to take the next dose at its scheduled time.

2.2Dosage 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 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 Any Severe or intolerable Withhold until improvement or resolution. Resume at a reduced dose upon improvement or resolution.

2.3Concomitant 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 . 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) . 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

2.4Concomitant 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 .

2.5Dosage 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 .

2.6Dosage 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 . TURALIO has not been studied in patients with severe hepatic impairment (total bilirubin >3 to 10 × ULN and any AST).

Embryo-Fetal Toxicity : May cause fetal harm. Advise patients of reproductive potential of the potential risk to a fetus and to use an effective non-hormonal method of contraception. ( 5.3 , 7.3 , 8.1 , 8.3 ) Potential Risks Associated with a High-Fat Meal : May increase incidence and severity of adverse reactions, including hepatotoxicity. Avoid taking TURALIO with a high-fat meal (approximately 55 to 65 grams of total fat). ( 2.1 , 5.4 )

5.1Hepatotoxicity

TURALIO can cause serious and potentially fatal liver injury and is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) . Hepatotoxicity, including liver failure and life-threatening vanishing bile duct syndrome (VBDS), ductopenia, and symptomatic cholestasis (including severe pruritus) can occur in patients treated with TURALIO and can occur despite monitoring and prompt drug cessation. The mechanism of cholestatic hepatotoxicity is unknown and its occurrence cannot be predicted. It is unknown whether liver injury can also occur in the absence of increased transaminases.

Of the first 609 patients who received TURALIO under the REMS program, 32 (5.3%) developed a liver injury event of concern (LIEC), defined as any serious liver-related outcome or any liver abnormality that triggers drug discontinuation per the US Prescribing Information . These 32 patients developed liver toxicity within 71 days of the first dose of TURALIO; ten required hospitalization, and two developed VBDS. Sixteen of the 32 patients had not fully recovered at the time of the analysis, including 6 patients followed for at least 6 months after discontinuation. Among 768 patients who received TURALIO in clinical trials, there were two irreversible cases of cholestatic liver injury. One patient with advanced cancer and ongoing liver toxicity died and one patient with a confirmed case of VBDS required a liver transplant.

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 three 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 . Refer patients to a hepatologist if liver tests do not return to normal. Rechallenge with a reduced dose of TURALIO may result in a recurrence of increased serum transaminases, bilirubin, ALP., or other signs of liver injury.

Monitor liver tests weekly for the first month after rechallenge.

5.2TURALIO

REMS Program TURALIO is only available through a restricted program under a REMS, because of the risk of hepatotoxicity . 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.

5.3Embryo-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 .

5.4Potential 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 . 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 .

None. None.

8.1Pregnancy Risk Summary Based on

findings from animal studies and its mechanism of action , TURALIO may cause embryo-fetal harm when administered to a pregnant woman. The available human data do not establish the presence or absence of major birth defects or miscarriage related to the use of TURALIO. Oral administration of pexidartinib to pregnant animals during the period of organogenesis resulted in malformations, post-implantation loss, and abortion at maternal exposures that were approximately equal to the human exposure at the recommended dose . 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.

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).

The following clinically significant adverse reactions are described elsewhere in the labeling: Hepatotoxicity . Most common adverse reactions (>20%) were increased lactate dehydrogenase, increased aspartate aminotransferase, hair color changes, fatigue, increased alanine aminotransferase, decreased neutrophils, increased cholesterol, increased alkaline phosphatase, decreased lymphocytes, eye edema, decreased hemoglobin, rash, dysgeusia, and decreased phosphate. To report SUSPECTED ADVERSE REACTIONS, contact Daiichi Sankyo, Inc. at 1-877-437-7763 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical 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 safety of TURALIO 250 mg orally twice 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 . The safety of TURALIO was evaluated in ENLIVEN . 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

4.03Grade

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

1.7Decreased

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), photosensitivity reactions.

6.2Postmarketing 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