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FDA News: Issue 23, August 2019

Published on 8/14/2019 8:02:00 AM


FDA Approves TURALIO (Pexidartinib) for Treatment of Adult Patients with Symptomatic Tenosynovial Giant Cell Tumor Associated with Severe Morbidity or Functional Limitations and Not Amenable to Improvement with Surgery     

On August 2, 2019, the US Food and Drug Administration (FDA) approved TURALIO (pexidartinib) for 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. The approved recommended dosage of TURALIO is 400 mg orally twice daily until disease progression or unacceptable toxicity. Administer TURALIO on an empty stomach, at least 1 hour before or 2 hours after a meal or snack.
 
TURALIO can cause serious and potentially fatal liver injury. 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 hepatoxicity. TURALIO is available only through a restricted Risk Evaluation and Mitigation Strategy (REMS) Program, because of the risk of hepatotoxicity. Advise patients of reproductive potential of the potential risk to a fetus and to use an effective method of contraception as TURALIO may cause fetal harm. Additional information regarding dosage and administration, warnings and precautions, the TURALIO REMS Program, dose modifications for adverse reactions, organ impairment, and concomitant drug use can be found in the full prescribing information below.
 
Mechanism of Action (MOA), Pharmacokinetics (PK), and Pharmacodynamics (PD)
  • MOA: Pexidartinib is a tyrosine kinase inhibitor.
  • General PK: Steady state pexidartinib maximum plasma concentration (Cmax)[mean (SD)]is 8625 ng/mL (2746) and area under the curve (AUC) is 77465 ng*h/mL (24975). Pexidartinib Cmax and AUCinf increased linearly over the single oral dose range of 200 to 2400 mg (0.5 to 6 times the recommended dose). Time to steady stateof pexidartinib is approximately 7 days, and the accumulation ratio for pexidartinib is 3.6.
  • Absorption: The median time to reach the peak plasma concentration (Tmax)of pexidartinib is 2.5 hours. Administration of a single dose of pexidartinib with food increased Cmax and AUCinf by 100%. Food delayed the Tmax by 2.5 hours.
  • Distribution: The plasma protein binding of pexidartinib is greater than 99%, in vitro. The plasma protein binding of pexidartinib to human serum albumin is 99.9% and to α-1 acid glycoprotein is 89.9%, in vitro. The apparent volume of distribution (Vz/F) [mean (% coefficient of variation (CV%))] of pexidartinib is 187 L (26.7%).
  • Elimination: The mean half-life (SD) of pexidartinib is 26.6 (6.5) hours. The apparent clearance [mean (CV%)] after a single oral dose of pexidartinib 400 mg is 5.14 L/h (36.3%).
  • Metabolism: Pexidartinib is primarily metabolized by oxidation (CYP3A) and glucuronidation (UGT1A4). The major inactive metabolite (N-glucuronide metabolite) of pexidartinib is formed by UGT1A4. There is approximately 10% higher exposure of N-glucuronide metabolite than pexidartinib after a single dose.
  • Excretion: Following a single oral dose of radiolabeled pexidartinib 400 mg, 65% of the administered dose was recovered in feces (44% as unchanged) and 27% as metabolites (≥10% as N-glucuronide) in urine.
  • PD: 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).
Drug Interactions
  • Use with Hepatotoxic Products: Avoid coadministration of TURALIO with other products known to cause hepatotoxicity in patients with increased serum transaminases, total bilirubin, direct bilirubin (>ULN), or active liver or biliary tract disease.
  • Strong CYP3A Inhibitors: Reduce TURALIO dosage if concomitant use of strong CYP3A inhibitors, including grapefruit or grapefruit juice, cannot be avoided.
  • Strong CYP3A Inducers: Avoid concomitant use of strong CYP3A inducers, including St. John's wort.
  • UGT Inhibitors: Reduce the dose of TURALIO if concomitant use of UGT inhibitors cannot be avoided.
  • Acid-Reducing Agents: Avoid concomitant use of proton pump inhibitors (PPIs) with TURALIO. Use histamine-2 receptor antagonists or antacids as alternatives to PPIs.
Use in Specific Populations
  • No clinically significant differences in the pharmacokinetics of pexidartinib were observed based on age (18 to 84 years), sex, or race/ethnicity (White and Black).
  • Renal Impairment: Reduce the recommended dosage of TURALIO for patients with mild to severe renal impairment (CLcr 15 to 89 mL/min, estimated by Cockcroft-Gault [C-G]).
  • Hepatic Impairment: No dosage adjustment for TURALIO is recommended for patients with mild (total bilirubin ≤ upper limit of normal [ULN] with AST > ULN or total bilirubin > 1 to 1.5 times ULN with any AST) hepatic impairment. The recommended dose of TURALIO has not been established for patients with moderate (total bilirubin > 1.5 to 3 times ULN and any AST) to severe (total bilirubin > 3 to 10 times ULN and any AST) hepatic impairment. 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 alkaline phosphatase.
  • Lactation: Advise women not to breastfeed during treatment with TURALIO and for at least one week after the final dose.
 
Efficacy and Safety 
Efficacy of TURALIO was demonstrated in 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. Patients were randomized to TURALIO 400 mg in the morning and 600 mg in the evening for 2 weeks followed by 400 mg twice daily or placebo. Additional information regarding the efficacy trial can be found in the full prescribing information linked below.
 
The most common adverse reactions included (>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.
 
Full prescribing information is available at https://go.usa.gov/xytdU.
Visit Drugs@FDA at http://go.usa.gov/cMsjT for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval. 

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Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA's MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), or by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).


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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.

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