TURALIO Capsule Ref.[10160] Active ingredients:

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 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 [see Drug Interactions (7.3), Use in Specific Populations (8.1, 8.3)].

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

• Hepatotoxicity [see Warnings and Precautions (5.1)].

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:

* 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.

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:

ALT = alanine aminotransferase; AST = aspartate aminotransferase; ALP = alkaline phosphatase

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:

LDH=Lactate Dehydrogenase
* Each test incidence is based on the number of patients who had both a baseline and at least one onstudy 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

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)

7.1 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. Effect of Other Drugs on TURALIO:

7.3 Effect of TURALIO on Other Drugs

Table 8. Effect of TURALIO on Other Drugs:

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).

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.

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

Pregnancy Testing

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

Contraception

Females

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 [see Drug Interactions (7.3), 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)].

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

Clinical studies of TURALIO did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

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)].

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)].