Turalio Drug Information

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

The recommended dosage of TURALIO is 250 mg taken orally twice daily with a low-fat meal (approximately 11 to 14 grams of total fat) until disease progression or unacceptable toxicity. Taking TURALIO with a high-fat meal (approximately 55 to 65 grams of total fat) increases pexidartinib concentrations and may increase the risk of adverse reactions, including hepatotoxicity. Swallow TURALIO capsules whole.

Do not open, break, or chew the capsules. If a patient vomits or misses a dose of TURALIO, instruct the patient to take the next dose at its scheduled time.

Dosage Modifications for Adverse Reactions

The recommended dose reductions for adverse reactions are provided in Table 1. Table 1: Recommended 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

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.

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).

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.

Dosage Modification for Renal Impairment

The recommended dosage of TURALIO for patients with mild to severe renal impairment (creatinine clearance 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.

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

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. The safety of TURALIO was evaluated in ENLIVEN.

ENLIVEN excluded patients with ALT, AST, or total bilirubin >1.5 × ULN; and known active or chronic infection with hepatitis B or C virus, or human immunodeficiency virus. Patients received TURALIO without food at a dose of 400 mg in the morning and 600 mg in the evening orally for 2 weeks followed by 400 mg orally twice daily until disease progression or unacceptable toxicity. Seventy-nine percent of patients received TURALIO for 6 months or longer and 66% for greater than one year.

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.

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 ( %) 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. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Investigations: Blood creatine phosphokinase increased

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.

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, 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. Strong CYP3A Inducers Clinical Impact Concomitant use of a strong CYP3A inducer decreases pexidartinib concentrations, which may decrease the efficacy of TURALIO.

Management Avoid concomitant use of strong CYP3A inducers, including St John's wort. Acid-Reducing Agents Clinical Impact Concomitant use of a PPI decreases pexidartinib concentrations, 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. High-Fat Meal Clinical Impact Taking TURALIO with a high-fat meal increased pexidartinib concentrations, which may increase the incidence and severity of TURALIO adverse reactions, including hepatotoxicity. 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).

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, which may reduce the efficacy of these substrates. Management Avoid coadministration of TURALIO with hormonal contraceptives.

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

Due to the high plasma protein binding, TURALIO is not expected to be dialyzable.