TURALIO® (pexidartinib) capsules

Gafacom May 05, 2023

TURALIO® (pexidartinib) capsules

TURALIO® (pexidartinib) capsules are a prescription medication used to treat symptomatic tenosynovial giant cell tumor (TGCT) in adults. TGCT is a rare type of non-cancerous tumor that affects the joints and tendon sheaths, causing pain and swelling. TURALIO works by targeting and inhibiting specific enzymes involved in the growth of these tumors. This helps to reduce the size of the tumor and relieve associated symptoms. TURALIO is taken orally in capsule form, typically twice daily with or without food

Pexidartinib is a kinase inhibitor. The chemical name of pexidartinib hydrochloride is 5-[(5-Chloro-1Hpyrrolo[ 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 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.

TURALIO® (pexidartinib) capsules


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.

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.

DOSAGE AND ADMINISTRATION

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.

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.

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.

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).

CONTRAINDICATIONS

None.

WARNINGS AND PRECAUTIONS

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).

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. 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.

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.

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.

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.

USE IN SPECIFIC POPULATIONS

Pregnancy: 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. Advise pregnant women of the potential risk to a fetus.

Lactation: 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.

Contraception: 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.

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.

Infertility: Based on findings from animal studies, TURALIO may impair both male and female fertility.

Pediatric Use: The safety and effectiveness of TURALIO in pediatric patients have not been established.

Geriatric Use: Clinical studies of TURALIO did not include sufficient numbers of subjects aged 65 and over todetermine whether they respond differently from younger subjects.

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]).

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).

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

OVERDOSAGE

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

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