The following clinically significant adverse reactions are described elsewhere in the labeling: Hepatotoxicity [see Warnings and Precautions (5.1) ]. Most common adverse reactions (>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.
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Daiichi Sankyo, Inc. at 1-877-437-7763 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical 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 [see Clinical Pharmacology (12.3) ].
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 TURALIO N=61 Placebo N=59 Adverse Reaction All Grades (%) Grade ≥ 3 (%) All Grades (%) Grade ≥ 3 (%) Skin and subcutaneous tissue Hair color changes 67 0 3.4 0 Rash Rash includes rash, maculo-papular rash, rash pruritic, urticaria, erythema, dermatitis acneiform, dermatitis allergic. 28 1.6 7 0 Pruritus Pruritis includes pruritus, pruritus generalized. 18 0 3.4 0 General Fatigue Fatigue includes fatigue, asthenia, malaise. 64 0 41 0 Peripheral edema Peripheral edema includes face edema, localized edema, edema peripheral, peripheral swelling. 20 0 7 0 Eye Eye edema Eye edema includes periorbital edema, eye edema, eyelid edema, papilledema. 30 1.6 5 0 Nervous system Dysgeusia Dysgeusia includes dysgeusia, ageusia. 26 0 1.7 0 Neuropathy Neuropathy includes neuropathy peripheral, paresthesia, hypoesthesia, burning sensation. 10 0 5 0 Gastrointestinal Vomiting 20 1.6 5 0 Constipation 12 0 5 0 Metabolism and nutrition Decreased appetite 16 0 10 0 Vascular Hypertension 15 4.9 10 0 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 TURALIO Each test incidence is based on the number of patients who had both a baseline and at least one on-study measurement TURALIO (n=61) and placebo (n=59).
Placebo Laboratory Abnormality Graded per NCI CTCAE v
1.7 Decreased platelets 15 0 5 0 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), photosensitivity reactions.
