Turalio
Pexidartinib hydrochloride · Capsule · Oral
Uses
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. ( 1 )
Dosage and administration
Recommended Dosage : 250 mg orally twice daily with a low-fat meal (approximately 11 to 14 grams of total fat). ( 2.1 ) See full prescribing information for dosage modifications due to adverse reactions, renal impairment and hepatic impairment. ( 2.2 , 2.5 , 2.6 ) 2.1 Recommended 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 [see Clinical Pharmacology (12.3) ] . 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 [see Warnings and Precautions (5.1 , 5.4) , Drug Interactions (7.2) , Clinical Pharmacology (12.2 , 12.3) ] . 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. 2.2 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) ] .
Dosage forms and strengths
Capsules: 125 mg, size 1 with white opaque body and powder blue opaque cap with black print "DSC521" Capsules: 125 mg ( 3 )
Contraindications
None. None. ( 4 )
Warnings and precautions
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 ) 5.1 Hepatotoxicity 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) [see Warnings and Precautions (5.2) ]. 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 [ see Dosage and Administration (2.2) ]. 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 [see Dosage and Administration (2.2) ] . 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. 5.2 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) ].
Side effects
The following clinically significant adverse reactions are described elsewhere in the labeling: Hepatotoxicity [see Warnings and Precautions (5.1) ]. 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. ( 6.1 ) 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. 6.1 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 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 [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).
Drug interactions
Use with Hepatotoxic Products : Avoid coadministration of TURALIO with other products known to cause hepatotoxicity. ( 7.1 ) Moderate or Strong CYP3A Inhibitors : Reduce the dose of TURALIO if concomitant use of moderate or strong CYP3A inhibitors cannot be avoided. ( 2.3 , 7.2 ) Strong CYP3A Inducers : Avoid concomitant use of strong CYP3A inducers. ( 7.2 ) UGT Inhibitors : Reduce the dose of TURALIO if concomitant use of UGT inhibitors cannot be avoided. ( 2.3 , 7.2 ) Acid-Reducing Agents : Avoid concomitant use of proton pump inhibitors. Use histamine-2 receptor antagonists or antacids if needed. ( 2.4 , 7.2 ) High-Fat Meal : Avoid taking TURALIO with a high-fat meal. ( 2.1 , 5.4 , 7.2 ). CYP3A Substrates : Avoid concomitant use with CYP3A substrates where minimal concentration changes may lead to serious therapeutic failure. ( 7.3 ) 7.1 Use with Hepatotoxic Products TURALIO can cause hepatotoxicity. In patients with increased serum transaminases, total bilirubin, 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.
Use in specific populations
Lactation : Advise not to breastfeed. ( 8.2 ) Renal Impairment : Reduce the dosage for patients with mild to severe renal impairment. ( 2.5 , 8.6 ) Hepatic Impairment : Reduce the dosage for patients with moderate hepatic impairment. ( 2.6 , 8.7 ) 8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1) ] , 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 (see Data ) . 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). 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).
Pregnancy
8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1) ] , 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 (see Data ) . 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).
Pediatric use
8.4 Pediatric Use The safety and effectiveness of TURALIO in pediatric patients have not been established.
Geriatric use
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.
Overdosage
Due to the high plasma protein binding, TURALIO is not expected to be dialyzable [see Clinical Pharmacology (12.3) ] .
Description
Pexidartinib is a kinase inhibitor. The chemical name of pexidartinib hydrochloride is 5-[(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-N-{[6-(trifluoromethyl)pyridin-3-yl]methyl}pyridin-2-amine monohydrochloride. Pexidartinib hydrochloride is an off-white to white solid. The molecular formula for pexidartinib hydrochloride is C 20 H 15 ClF 3 N 5 ∙HCl. The molecular weight is 454.28 for the hydrochloride salt and 417.81 for the free base. The chemical structure is: The solubility of pexidartinib hydrochloride in aqueous solutions decreases with increasing pH. The pKa1 and pKa2 were determined to be 2.6 and 5.4 respectively for the conjugate acids. Pexidartinib hydrochloride is soluble in methanol, slightly soluble in water and ethanol, and practically insoluble in heptane. TURALIO (pexidartinib) capsules are for oral use. Each capsule contains 125 mg pexidartinib which is equivalent to 135.9 mg pexidartinib hydrochloride. The capsule contains the following inactive ingredients: poloxamer 407, mannitol, crospovidone, and magnesium stearate. The hypromellose capsule shell contains hypromellose, titanium dioxide and FD&C Blue No. 1. Chemical Structure
Mechanism of action
12.1 Mechanism of Action Pexidartinib is a small molecule tyrosine kinase inhibitor that targets colony stimulating factor 1 receptor (CSF1R), KIT proto-oncogene receptor tyrosine kinase (KIT), and FMS-like tyrosine kinase 3 (FLT3) harboring an internal tandem duplication (ITD) mutation. Overexpression of the CSF1R ligand promotes cell proliferation and accumulation in the synovium. In vitro, pexidartinib inhibited proliferation of cell lines dependent on CSF1R and ligand-induced autophosphorylation of CSF1R. Pexidartinib also inhibited the proliferation of a CSF1R dependent cell line in vivo.
How supplied
125 mg capsules are supplied as size 1 with white opaque body and powder blue opaque cap with black print "DSC521", available in: 28 count bottle 120 count bottle NDC#: 65597-407-28 NDC#: 65597-407-20 Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Keep containers closed and do not remove desiccant from bottles.
Storage
Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Keep containers closed and do not remove desiccant from bottles.
Patient information
Advise the patient to read the FDA-approved patient labeling (Medication Guide). Hepatotoxicity Advise patients of the risk of hepatotoxicity that could be fatal and that they will need to undergo monitoring for liver injury. Advise patients to immediately report any signs or symptoms of severe liver injury to their healthcare provider and that liver testing and prompt cessation of TURALIO may not eliminate the risk of severe or life-threatening liver injury [see Warnings and Precautions (5.1) ] . TURALIO REMS Program TURALIO is available only through a restricted program called TURALIO REMS Program and patients are required to be part of the patient registry [see Warnings and Precautions (5.2) ] . TURALIO is available only from certified pharmacies participating in the program. Therefore, provide patients with the telephone number and website for information on how to obtain the product. Embryo-Fetal Toxicity Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known 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) ] . Photosensitivity Inform patients of the signs and symptoms of photosensitivity. Advise patients to avoid prolonged sun exposure and to use sunscreen and protective clothing during treatment with TURALIO [see Adverse Reactions (6.1) ].
Label text from the FDA structured product label by Daiichi Sankyo Inc. (revised Jan 16, 2025). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Pexidartinib Hydrochloride in 1 product
Turalio NDC products (1)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 65597-407 | Pexidartinib Hydrochloride 125 mg/1 Capsule | Daiichi Sankyo Inc. | NDA |
Frequently asked questions
What is Turalio used for?
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…
What are the side effects of Turalio?
The following clinically significant adverse reactions are described elsewhere in the labeling: Hepatotoxicity [see Warnings and Precautions (5.1) ]. 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… See the full label for the complete list.
Who makes Turalio?
Turalio is listed by 1 labeler in the FDA NDC directory, including Daiichi Sankyo Inc..