Turalio

• TURALIO can cause serious and potentially fatal liver injury, including vanishing bile duct syndrome

  [see

  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.

  ]

  .
• Monitor liver tests prior to initiation of TURALIO and at specified intervals during treatment. Withhold and dose reduce or permanently discontinue TURALIO based on severity of hepatotoxicity. Monitoring and prompt cessation of TURALIO may not eliminate the risk of serious and potentially fatal liver injury

  [see

  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 ALPConfirm 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.

  ,

  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.

  ]

  .
• TURALIO is available only through a restricted program called the TURALIO Risk Evaluation and Mitigation Strategy (REMS) Program

  [see

  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.

  ]

  .

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.

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

  The recommended dosage of TURALIO for patients with mild to severe renal impairment (creatinine clearance [CLcr] 15 to 89 mL/min estimated by Cockcroft-Gault using actual body weight) is 125 mg in the morning and 250 mg in the evening with a low-fat meal

  [see Clinical Pharmacology (12.3)]

  .
  ,
  2.6 Dosage Modification for Hepatic Impairment

  The recommended dosage of TURALIO for patients with moderate hepatic impairment (total bilirubin >1.5 to 3 × upper limit of normal (ULN), not due to Gilbert's syndrome, with any AST) is 125 mg twice daily with a low-fat meal

  [see Clinical Pharmacology (12.3)]

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

Capsules: 125 mg, size 1 with white opaque body and powder blue opaque cap with black print "DSC521"

• Lactation
  : Advise not to breastfeed. (
  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.
  )
• Renal Impairment
  : Reduce the dosage for patients with mild to severe renal impairment. (
  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)]

  .
  ,
  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)]

  .
  )
• Hepatic Impairment
  : Reduce the dosage for patients with moderate hepatic impairment. (
  2.6 Dosage Modification for Hepatic Impairment

  The recommended dosage of TURALIO for patients with moderate hepatic impairment (total bilirubin >1.5 to 3 × upper limit of normal (ULN), not due to Gilbert's syndrome, with any AST) is 125 mg twice daily with a low-fat meal

  [see Clinical Pharmacology (12.3)]

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