TURALIO- pexidartinib capsule

Turalio by

Drug Labeling and Warnings

Turalio by is a Prescription medication manufactured, distributed, or labeled by Daiichi Sankyo Inc.. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

  • BOXED WARNING (What is this?)

    WARNING: HEPATOTOXICITY

  • 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.

  • 2 DOSAGE AND ADMINISTRATION

    2.1 Important Administration Instructions

    Administer TURALIO on an empty stomach, at least one hour before or two hours after a meal or snack [see Warnings and Precautions (5.1), Clinical Pharmacology (12.2, 12.3)].

    2.2 Recommended Dosage

    The recommended dosage of TURALIO is 400 mg taken twice daily on an empty stomach until disease progression or unacceptable toxicity [see Dosage and Administration (2.1), Clinical Pharmacology (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.

    2.3 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 ReductionTotal Daily DoseAdministration of Total Daily Dose
    First600 mg200 mg in the morning and 400 mg in the evening
    Second400 mg200 mg twice daily

    Permanently discontinue TURALIO in patients who are unable to tolerate 200 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 ReactionSeverityTURALIO 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
  • * Confirm ALP elevations as liver isozyme fraction.
  • Hepatotoxicity [see Warnings and Precautions (5.1)]
    Increased ALT and/or ASTGreater 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* and GGTALP 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 bilirubinTB 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)]
    AnySevere or intolerable
    • Withhold until improvement or resolution.
    • Resume at a reduced dose upon improvement or resolution.

    2.4 Concomitant Use of Strong CYP3A Inhibitors or UGT Inhibitors

    Avoid concomitant use of TURALIO with strong CYP3A inhibitors or UGT inhibitors during treatment with TURALIO. If concomitant use with a 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 strong CYP3A inhibitor or UGT inhibitor is discontinued, increase the TURALIO dose (after 3 plasma half-lives of the 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 Strong CYP3A Inhibitors or UGT Inhibitors
    Planned Total Daily DoseModified Total Daily DoseAdministration of Modified Total Daily Dose
  • * Planned total daily dose refers to recommended dose reductions for TURALIO for adverse reactions based on dosing recommendations in Table 2.
  • 800 mg400 mg200 mg twice daily
    600 mg*400 mg200 mg twice daily
    400 mg*200 mg200 mg once daily

    2.5 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 (H2)-receptor antagonist, administer TURALIO at least 2 hours before or 10 hours after taking an H2-receptor antagonist [see Clinical Pharmacology (12.3)].

    2.6 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 200 mg in the morning and 400 mg in the evening [see Clinical Pharmacology (12.3)].

  • 3 DOSAGE FORMS AND STRENGTHS

    Capsules: 200 mg, size 0 with white opaque body and dark green opaque cap with white print "T10"

  • 4 CONTRAINDICATIONS

    None.

  • 5 WARNINGS AND PRECAUTIONS

    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 with ductopenia and cholestasis occurred in patients treated with TURALIO. Across 768 patients who received TURALIO in clinical trials, there were two irreversible cases of cholestatic liver injury. One patient died with advanced cancer and ongoing liver toxicity and one patient required 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. Taking TURALIO with food increases drug exposure by 100% and may increase the risk of hepatotoxicity. Administer TURALIO on an empty stomach, either 1 hour before or 2 hours after a meal or snack [see Dosage and Administration (2.1), Clinical Pharmacology (12.2, 12.3)]. 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 of 800 mg 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 contraception 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 Use in Specific Populations (8.1, 8.3)].

  • 6 ADVERSE REACTIONS

    The following clinically significant adverse reactions are described elsewhere in the labeling:

    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 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 ReactionAll Grades
    (%)
    Grade ≥ 3
    (%)
    All Grades
    (%)
    Grade ≥ 3
    (%)
  • * Rash includes rash, maculo-papular rash, rash pruritic, urticaria, erythema, dermatitis acneiform, dermatitis allergic.
  • Pruritis includes pruritus, pruritus generalized.
  • Fatigue includes fatigue, asthenia, malaise.
  • § Peripheral edema includes face edema, localized edema, edema peripheral, peripheral swelling.
  • Eye edema includes periorbital edema, eye edema, eyelid edema, papilledema.
  • # Dysgeusia includes dysgeusia, ageusia.
  • Þ Neuropathy includes neuropathy peripheral, paresthesia, hypoesthesia, burning sensation.
  • Skin and subcutaneous tissue
    Hair color changes6703.40
    Rash*281.670
    Pruritus1803.40
    General
    Fatigue640410
    Peripheral edema§20070
    Eye
    Eye edema301.650
    Nervous system
    Dysgeusia#2601.70
    NeuropathyÞ10050
    Gastrointestinal
    Vomiting201.650
    Constipation12050
    Metabolism and nutrition
    Decreased appetite160100
    Vascular
    Hypertension154.9100
    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*Placebo*
    Laboratory AbnormalityGrade 1
    (%)
    Grade 2
    (%)
    Grade ≥ 3
    (%)
    Grade 1
    (%)
    Grade 2
    (%)
    Grade ≥ 3
    (%)
    ALT = alanine aminotransferase; AST = aspartate aminotransferase; ALP = alkaline phosphatase
  • * 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).
  • Graded per NCI CTCAE v 4.03
  • Liver Tests
    Increased AST6115121500
    Increased ALT3113202200
    Increased ALP313.34.91.700
    Increased bilirubin3.33.33.3000
    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*Placebo*
    Laboratory AbnormalityAll Grades
    (%)
    Grade ≥3
    (%)
    All Grades
    (%)
    Grade ≥3
    (%)
    LDH=Lactate Dehydrogenase
  • * 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).
  • Graded per NCI CTCAE v 4.03 except for 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
  • Chemistry
    Increased LDH92050
    Increased cholesterol444.9250
    Decreased phosphate253.350
    Hematology
    Decreased neutrophils443.390
    Decreased lymphocytes381.63.40
    Decreased hemoglobin300141.7
    Decreased platelets15050

    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)

  • 7 DRUG INTERACTIONS

    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 on TURALIO

    Table 7: Clinically Important Drug Interactions with TURALIO
    Strong CYP3A Inhibitors
    Clinical Impact
    • Concomitant use of a strong CYP3A inhibitor increases pexidartinib plasma 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 strong CYP3A inhibitors, including grapefruit or grapefruit juice, cannot be avoided [see Dosage and Administration (2.4)].
    Strong CYP3A Inducers
    Clinical Impact
    • Concomitant use of a strong CYP3A inducer decreases pexidartinib plasma 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 plasma concentrations [see Clinical Pharmacology (12.3)], which may increase the incidence and severity of adverse reactions of TURALIO.
    Management
    Acid-Reducing Agents
    Clinical Impact
    • Concomitant use of a PPI decreases pexidartinib plasma 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 H2-receptor antagonists [see Dosage and Administration (2.5)].
  • 8 USE IN SPECIFIC POPULATIONS

    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 of 800 mg (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 of 800 mg). 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 of 800 mg).

    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 one week after the final dose.

    8.3 Females and Males of Reproductive Potential

    Pregnancy Testing

    Verify pregnancy status in females of reproductive potential prior to the initiation of TURALIO [see Use in Specific Populations (8.1)].

    Contraception

    TURALIO may cause embryo-fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

    Females

    Advise females of reproductive potential to use effective contraception during treatment with TURALIO and for 1 month after the final dose [see 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 dose 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 (2.6), Clinical Pharmacology (12.3)].

    8.7 Hepatic Impairment

    No dosage adjustment is recommended for patients with mild hepatic impairment (total bilirubin less than or equal to upper limit of normal [ULN] with AST greater than ULN or total bilirubin greater than 1 to 1.5 times ULN with any AST) [see Clinical Pharmacology (12.3)].

    The recommended dose of TURALIO has not been established for patients with moderate (total bilirubin greater than 1.5 to 3 times ULN and any AST) to severe (total bilirubin greater than 3 to 10 times ULN and any AST) hepatic impairment [see Warnings and Precautions (5.1)].

  • 10 OVERDOSAGE

    Due to the high plasma protein binding, TURALIO is not expected to be dialyzable [see Clinical Pharmacology (12.3)].

  • 11 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 C20H15ClF3N5∙HCl. The molecular weight is 454.28 for the hydrochloride salt and 417.81 for the free base. The chemical structure is:

    Chemical Structure

    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 200 mg pexidartinib which is equivalent to 217.5 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, black iron oxide and yellow iron oxide.

  • 12 CLINICAL PHARMACOLOGY

    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.

    12.2 Pharmacodynamics

    Exposure-Response Relationships

    There is an exposure response relationship between pexidartinib steady state exposure and serum transaminase levels (ALT and AST) with a higher risk of increased serum transaminases at higher exposure. Additionally, increased transaminases occurred more frequently with higher pexidartinib doses (200 to 1200 mg per day).

    Cardiac Electrophysiology

    At two times the mean maximum exposure of the 400 mg twice daily dose, 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 8.

    Table 8: TURALIO Exposure and Pharmacokinetic Parameters
  • * Pexidartinib 400 mg twice daily
  • Estimated based on half life
  • The high fat meal comprised 800 to 1000 calories with fat being 50% of total caloric content; approximately 150 calories from protein, 250 calories from carbohydrates, and 500-600 calories from fat.
  • § After a single oral dose of pexidartinib 400 mg
  • After a single oral dose of radiolabeled pexidartinib 400 mg
  • General Information
    Steady state exposure [Mean (SD)]*Cmax8625 (2746) ng/mL
    AUC0-12h77465 (24975) ng∙h/mL
    Dose proportionalityPexidartinib exposure (Cmax and AUC0-INF) increased linearly over the single oral dose range of 200 to 2400 mg (0.5 to 6 times the recommended dose).
    Time to steady stateApproximately 7 days
    Accumulation ratio (AUC) [Median] 3.6
    Absorption
    Tmax [Median]2.5 hours
      Effect of food
      Administration with high fat meal
    • Increased pexidartinib Cmax and AUC0-INF by 100%
    • Delayed Tmax by 2.5 hours
    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%)]§
    • 187 L (27%)
    Elimination
    Apparent clearance [Mean (CV%)]§
    • 5.1 L/h (36%)
    t1/2 [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
    • 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

    The pharmacokinetics of pexidartinib has not been adequately characterized in patients with moderate hepatic impairment (total bilirubin > 1.5 to 3 × ULN and any AST) or studied in patients with severe hepatic impairment (total bilirubin > 3 to 10 × ULN and any AST).

    Drug Interaction Studies

    Clinical Studies

    Effect of Strong CYP3A Inducers on Pexidartinib: Coadministration of rifampicin (a strong CYP3A inducer) decreased pexidartinib Cmax by 33% and AUC by 65% [see Drug Interactions (7.2)]. The effect of coadministration with a moderate CYP3A inducer on pexidartinib pharmacokinetics is not known.

    Effect of Strong CYP3A Inhibitors on Pexidartinib: Coadministration of itraconazole (a strong CYP3A inhibitor) increased pexidartinib Cmax by 48% and AUC by 70% [see Drug Interactions (7.2)]. The effect of coadministration with a moderate CYP3A inhibitor on pexidartinib pharmacokinetics is not known.

    Effect of UGT Inhibitors on Pexidartinib: Coadministration of probenecid (a UGT inhibitor) increased pexidartinib Cmax by 5% and AUC by 60% [see Drug Interactions (7.2)].

    Effect of Acid-Reducing Agents on Pexidartinib: Coadministration of esomeprazole (a proton pump inhibitor) decreased pexidartinib Cmax by 55% and AUC by 50% [see Drug Interactions (7.2)]. The effects of H2-receptor antagonists and locally-acting antacids on pexidartinib pharmacokinetics have not been studied.

    Effect of Pexidartinib on CYP2C19 Substrates: Coadministration of a single oral dose of TURALIO 1800 mg decreased omeprazole (CYP2C19 substrate) Cmax by 37% and AUC by 17% compared to omeprazole alone.

    Effect of Pexidartinib on P-gp Substrates: Coadministration of a single oral dose of TURALIO 1800 mg increased digoxin (P-gp substrate) Cmax by 30% and AUC by 9% compared to digoxin alone.

    Effect of Pexidartinib on CYP2C8 Substrates: Based on modeling and simulation, pexidartinib is predicted to have negligible interaction potential with CYP2C8 substrates at clinically relevant concentrations.

    In Vitro Studies

    Effects of Pexidartinib on CYP Enzymes: Pexidartinib is likely to inhibit CYP2B6, 2C9, and 3A4 and induce CYP3A and 2B6 at clinically relevant concentrations.

    Effect of Pexidartinib on UGT: Pexidartinib is likely to inhibit UGT1A1 at clinically relevant concentrations.

    Pexidartinib as a Substrate for Transporters: Pexidartinib is not a substrate for P-gp, BCRP, OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, OATP2B1, and BSEP.

    Effect of Pexidartinib on Transporters: Pexidartinib inhibits the transport activities of MATE1, MATE2-K, OATP1B1, OATP1B3 and OATP2B1.

  • 13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

    Carcinogenicity studies were performed in mice and rats. Both studies were negative for carcinogenic findings at exposures up to 9 times the human exposure at the recommended daily dose of 800 mg based on AUC.

    Pexidartinib was not mutagenic in an in vitro bacterial reverse mutation (AMES) assay or clastogenic in either an in vitro human peripheral blood lymphocyte chromosomal aberrations assay or in an in vivo mouse bone marrow micronucleus assay.

    Based on nonclinical findings, TURALIO may impair male and female fertility. In a fertility study in which pexidartinib was administered orally to male and female rats, there were reductions in pregnancy, as well as increases in pre- and post-implantation loss with a corresponding reduction in viable embryos at 40 mg/kg (approximately 1.3 times the human exposure at the recommended dose of 800 mg). Males at this dose level displayed reductions in spermatogenic parameters and adverse 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 of 800 mg). 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 of 800 mg). 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 of 800 mg).

    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 of 800 mg) 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 of 800 mg). 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 of 800 mg).

    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 of 800 mg). 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 of 800 mg). 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.

  • 14 CLINICAL STUDIES

    14.1 Tenosynovial Giant Cell Tumor

    The efficacy of TURALIO was evaluated in ENLIVEN (NCT02371369), a double-blind, randomized (1:1), placebo-controlled, multicenter trial in patients with symptomatic TGCT [also referred to as giant cell tumor of the tendon sheath (GCT-TS) or pigmented villonodular synovitis (PVNS)] for whom surgical removal of the tumor would be associated with worsening functional limitation or severe morbidity. Eligible patients were required to have measurable disease per the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Patients were randomized to placebo or TURALIO 400 mg in the morning and 600 mg in the evening for 2 weeks followed by 400 mg twice daily. Treatment continued 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).

    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 9.

    Table 9: Efficacy Results Assessed at Week 25 for ENLIVEN
    Efficacy ParameterTURALIO
    N=61
    Placebo
    N=59
    CI: confidence interval; NA: not applicable; SD: standard deviation; LS: least squares; +: denotes ongoing at last assessment
  • * Blinded independent central review
  • Data cut-off date January 31, 2018
  • Fisher's exact test
  • Overall Response Rate (ORR)*,
    ORR
    (95% CI)
    38%
    (27%, 50%)
    0
    (0, 6%)
      Complete Response15%0
      Partial Response23%0
    P-value<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                                 

    Figure 1

    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.

  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    TURALIO 200 mg capsules are supplied as size 0 with white opaque body and dark green opaque cap with white print "T10", available in:

    28 count bottleNDC#: 65597-402-28
    120 count bottleNDC#: 65597-402-20

    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.

  • 17 PATIENT COUNSELING 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 and to report immediately any signs or symptoms of severe liver injury to their healthcare provider [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

    Lactation

    Advise females not to breastfeed during treatment with TURALIO and for one 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)].

    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)].

    Administration

    Instruct patients to take TURALIO on an empty stomach (at least 1 hour before or 2 hours after a meal or snack). Instruct patients to swallow capsules whole (do not open, break, or chew) [see Dosage and Administration (2.1, 2.2)].

  • SPL UNCLASSIFIED SECTION

    Manufactured for: Daiichi Sankyo, Inc.
    Basking Ridge, NJ 07920

    TURALIO™ is a trademark of Daiichi Sankyo Company, Limited.
    ©2019, Daiichi Sankyo, Inc.

    USPI-TUR-0819-r001

  • MEDICATION GUIDE

    This Medication Guide has been approved by the U.S. Food and Drug Administration.Issued:08/2019    
    Medication Guide
    TURALIO (tur-a-lee-oh)
    (pexidartinib)
    Capsules
    What is the most important information I should know about TURALIO?
    TURALIO can cause serious side effects, including:
    Serious Liver Problems which may be severe and can lead to death.

    Your healthcare provider will do blood tests to check for liver problems:
    • before starting treatment with TURALIO,
    • every week for the first 8 weeks during treatment,
    • every 2 weeks for the next month,
    • then, every 3 months after that.
    If you develop liver problems during treatment with TURALIO, your healthcare provider may do blood tests more often to monitor you. It is important to stay under the care of your healthcare provider during treatment with TURALIO.
    Stop taking TURALIO and call your healthcare provider right away if you develop:
    • yellowing of your skin and whites of your eyes
    • dark urine
    Tell your healthcare provider right away if you have any of these symptoms of liver problems while taking TURALIO:
    • lack or loss of appetite
    • right upper stomach-area (abdomen) pain or tenderness
    • feeling overly tired
    • nausea
    • vomiting
    • fever
    • rash
    • itching
    TURALIO Risk Evaluation and Mitigation Strategy (REMS): Because of the risk of serious liver problems, TURALIO is available only through a restricted program called the TURALIO REMS Program. Your healthcare provider must be enrolled in the program in order for you to be prescribed TURALIO. There is a registry that collects information about the effects of taking TURALIO over time. You must complete and sign an enrollment form for the TURALIO REMS Program and the registry. Ask your healthcare provider for more information.
    What is TURALIO?
    TURALIO is a prescription medicine used to treat certain adults who have tenosynovial giant cell tumor (TGCT) that is not likely to improve with surgery. TGCT is also known as giant cell tumor of the tendon sheath (GCT-TS) or pigmented villonodular synovitis (PVNS).
    It is not known if TURALIO is safe and effective in children.
    Before taking TURALIO, tell your healthcare provider about all of your medical conditions, including if you:
    • have or had liver problems.
    • are pregnant or plan to become pregnant. TURALIO may harm your unborn baby.
      If you are a female who is able to become pregnant:
      • Your healthcare provider will do a pregnancy test before you start treatment with TURALIO.
      • Use an effective method of birth control (contraception) during treatment with TURALIO and for 1 month after your final dose of TURALIO. Talk with your healthcare provider about birth control methods you can use during this time.
      • Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with TURALIO.
      If you are a male with a female partner who is able to become pregnant:
      • Use effective birth control (contraception) during treatment and for 1 week after your final dose of TURALIO.
      • Tell your healthcare provider right away if your female partner becomes pregnant or thinks she is pregnant during your treatment with TURALIO.
    • are breastfeeding or plan to breastfeed. Do not breastfeed during treatment with TURALIO and for at least 1 week after your final dose of TURALIO.
    Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Certain medicines may affect the way TURALIO works and TURALIO may affect how other medicines work. Taking TURALIO with certain medicines can increase the amount of TURALIO in your blood. This may make it more likely for you to have side effects and may cause more severe side effects.
    • Avoid taking the following medicines or supplements during treatment with TURALIO because they can affect how TURALIO works:
      • Proton Pump Inhibitor medicines (PPIs)
      • St. John's wort
    How should I take TURALIO?
    • Your healthcare provider will explain to you how you will receive your TURALIO.
    • Take TURALIO exactly as your healthcare provider tells you to.
    • TURALIO is usually taken 2 times a day. Your healthcare provider will tell you how much TURALIO to take and when to take it.
    • TURALIO must be taken on an empty stomach, at least 1 hour before or 2 hours after eating a meal or snack.
    • Swallow TURALIO capsules whole.
    • Do not open, break, or chew TURALIO capsules.
    • If you need to take an acid-reducing medicine, follow your healthcare provider's instructions for which medicine to take and when to take it. See "What should I avoid while taking TURALIO?"
      • Antacid medicines: Take TURALIO either 2 hours before or 2 hours after taking an antacid medicine.
      • H2 receptor blocker medicines. Take TURALIO at least 2 hours before or 10 hours after taking an H2 receptor blocker medicine.
    • If you vomit after taking a dose, or if you miss a dose of TURALIO, take your next dose at your regular time.
    What should I avoid while taking TURALIO?
    • Avoid drinking grapefruit juice during treatment with TURALIO. Grapefruit juice can cause you to have too much TURALIO in your blood and may lead to increased side effects and more severe side effects.
    What are the possible side effects of TURALIO?
    TURALIO can cause serious side effects. See "What is the most important information I should know about TURALIO?"

    The most common side effects of TURALIO include:
    • changes in blood liver tests
    • hair color changes
    • tiredness
    • increased cholesterol level in your blood
    • decreased white blood cells and red blood cells
    • swelling in or around your eyes
    • rash
    • loss of taste or changes in the way things taste
    TURALIO may affect fertility in females and males, which may affect your ability to have children. Talk to your healthcare provider if you have concerns about fertility.
    These are not all of the possible side effects of TURALIO.
    Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
    How should I store TURALIO?
    • Store TURALIO at room temperature between 68°F to 77°F (20°C to 25°C).
    • Keep the TURALIO container closed tightly.
    • TURALIO comes with a drying agent (desiccant) in the container. Keep the desiccant in the container.
    Keep TURALIO and all medicines out of the reach of children.
    General information about the safe and effective use of TURALIO
    Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use TURALIO for a condition for which it was not prescribed. Do not give TURALIO to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about TURALIO that is written for health professionals.
    What are the ingredients in TURALIO?
    Active Ingredient:
    pexidartinib
    Inactive Ingredients: poloxamer 407, mannitol, crospovidone, and magnesium stearate. Capsule shell: hypromellose, titanium dioxide, black iron oxide and yellow iron oxide
    Manufactured for: Daiichi Sankyo, Inc., Basking Ridge, NJ 07920
    TURALIO™ is a trademark of Daiichi Sankyo Company, Limited. ©2019, Daiichi Sankyo, Inc.
    MG-TUR-0819-r001
    For more information, call 1-877-437-7763 or go to www.turalio.com.
  • PRINCIPAL DISPLAY PANEL - 120 Capsule Bottle Carton

    NDC: 65597-402-20
    Rx only

    Turalio
    (pexidartinib)
    capsules

    200 mg

    120 capsules

    for oral use

    Dispense the accompanying
    Medication Guide to each patient.

    Daiichi-Sankyo

    PRINCIPAL DISPLAY PANEL - 120 Capsule Bottle Carton
  • PRINCIPAL DISPLAY PANEL - 28 Capsule Bottle Carton

    NDC: 65597-402-28
    Rx only

    Turalio
    (pexidartinib)
    capsules

    200 mg

    28 capsules

    for oral use

    Dispense the accompanying
    Medication Guide to each patient.

    Daiichi-Sankyo

    PRINCIPAL DISPLAY PANEL - 28 Capsule Bottle Carton
  • INGREDIENTS AND APPEARANCE
    TURALIO 
    pexidartinib capsule
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 65597-402
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    PEXIDARTINIB HYDROCHLORIDE (UNII: YS6WAI3XN7) (PEXIDARTINIB - UNII:6783M2LV5X) PEXIDARTINIB200 mg
    Inactive Ingredients
    Ingredient NameStrength
    POLOXAMER 407 (UNII: TUF2IVW3M2)  
    MANNITOL (UNII: 3OWL53L36A)  
    CROSPOVIDONE, UNSPECIFIED (UNII: 2S7830E561)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)  
    TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
    FERROSOFERRIC OXIDE (UNII: XM0M87F357)  
    FERRIC OXIDE YELLOW (UNII: EX438O2MRT)  
    Product Characteristics
    ColorWHITE (white opaque body) , GREEN (Dark green opaque cap) Scoreno score
    ShapeCAPSULESize21mm
    FlavorImprint Code T10
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 65597-402-201 in 1 CARTON08/02/2019
    1120 in 1 BOTTLE; Type 0: Not a Combination Product
    2NDC: 65597-402-281 in 1 CARTON08/02/2019
    228 in 1 BOTTLE; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    NDANDA21181008/02/2019
    Labeler - Daiichi Sankyo Inc. (068605067)

  • Trademark Results [Turalio]

    Mark Image

    Registration | Serial
    Company
    Trademark
    Application Date
    TURALIO
    TURALIO
    88493474 not registered Live/Pending
    DAIICHI SANKYO COMPANY, LIMITED
    2019-06-28
    TURALIO
    TURALIO
    79218633 5537820 Live/Registered
    DAIICHI SANKYO COMPANY, LIMITED
    2017-07-26

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