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The following adverse reactions are discussed in greater detail in other sections of the labeling:

  • Bullous and Exfoliative Skin Disorders [see WARNINGS AND PRECAUTIONS]
  • Interstitial Lung Disease [see WARNINGS AND PRECAUTIONS]
  • Hepatic Toxicity [see WARNINGS AND PRECAUTIONS]

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 evaluation of GILOTRIF is based on the data from more than 3800 patients, including 2135 NSCLC patients receiving GILOTRIF monotherapy at or above the recommended dose.

Controlled Study

The data in Tables 1 and 2 below reflect exposure of 229 EGFR-TKI naïve GILOTRIF-treated patients with EGFR mutation-positive, metastatic, non-squamous, NSCLC enrolled in a randomized, multicenter, open-label trial (Study 1). Patients received GILOTRIF 40 mg daily until documented disease progression or intolerance to the therapy. A total of 111 patients were treated with pemetrexed/cisplatin. Patients were treated with pemetrexed 500 mg/m² followed after 30 minutes by cisplatin 75 mg/m² every three weeks for a maximum of six treatment courses.

The median exposure was 11.0 months for patients treated with GILOTRIF and 3.4 months for patients treated with pemetrexed/cisplatin. The overall trial population had a median age of 61 years; 61% of patients in the GILOTRIF arm and 60% of patients in the pemetrexed/cisplatin arm were younger than 65 years. A total of 64% of patients on GILOTRIF and 67% of pemetrexed/cisplatin patients were female. More than two-thirds of patients were from Asia (GILOTRIF 70%; pemetrexed/cisplatin 72%).

Serious adverse reactions were reported in 29% of patients treated with GILOTRIF. The most frequent serious adverse reactions reported in patients treated with GILOTRIF were diarrhea (6.6%); vomiting (4.8%); and dyspnea, fatigue, and hypokalemia (1.7% each). Fatal adverse reactions in GILOTRIF-treated patients in Study 1 included pulmonary toxicity/ILD-like adverse reactions (1.3%), sepsis (0.43%), and pneumonia (0.43%).

Dose reductions due to adverse reactions were required in 57% of GILOTRIF-treated patients. The most frequent adverse reactions that led to dose reduction in the patients treated with GILOTRIF were diarrhea (20%), rash/acne (19%), paronychia (14%), and stomatitis (10%).

Discontinuation of therapy in GILOTRIF-treated patients for adverse reactions was 14.0%. The most frequent adverse reactions that led to discontinuation in GILOTRIF-treated patients were diarrhea (1.3%), ILD (0.9%), and paronychia (0.9%).

Clinical trials of GILOTRIF excluded patients with an abnormal left ventricular ejection fraction (LVEF), i.e., below the institutional lower limit of normal. In Study 1, all patients were evaluated for LVEF at screening and every 9 weeks thereafter in the GILOTRIF-treated group and as needed in the pemetrexed/cisplatin group. More GILOTRIF-treated patients (2.2%; n=5) experienced ventricular dysfunction (defined as diastolic dysfunction, left ventricular dysfunction, or ventricular dilation; all < Grade 3) compared to chemotherapy-treated patients (0.9%; n=1).

Table 1 : Adverse Reactions Reported in ≥ 10% of GILOTRIF-Treated Patients in Study 1

Adverse Reaction GILOTRIF
Pemetrexed/ Cisplatin
All Grades (%) Grade 3* (%) All Grades (%) Grade 3* (%)
Gastrointestinal disorders
  Diarrhea 96 15 23 2
  Stomatitis1 71 9 15 1
  Cheilitis 12 0 1 0
Skin and subcutaneous tissue disorders
  Rash/Dermatitis acneiform2 90 16 11 0
  Pruritus 21 0 1 0
  Dry skin 31 0 2 0
Infections and infestations
  Paronychia3 58 11 0 0
  Cystitis 13 1 5 0
Metabolism and nutrition disorders
  Decreased appetite 29 4 55 4
Respiratory, thoracic and mediastinal disorders
  Epistaxis 17 0 2 1
  Rhinorrhea 11 0 6 0
  Weight decreased 17 1 14 1
General disorders and administration site conditions
  Pyrexia 12 0 6 0
Eye disorders  
  Conjunctivitis 11 0 3 0
*None of the adverse reactions in this table except stomatitis (one patient on GILOTRIF [0.4%]) were Grade 4 in severity.
1Includes stomatitis, aphthous stomatitis, mucosal inflammation, mouth ulceration, oral mucosa erosion, mucosal erosion, mucosal ulceration
2Includes group of rash preferred terms, acne, acne pustular, dermatitis acneiform
3Includes paronychia, nail infection, nail bed infection

Table 2 : Adverse Reactions of Laboratory Abnormalities from the Investigations SOC Reported in ≥ 5% of GILOTRIF-Treated Patients in Study 1

Adverse Reaction GILOTRIF
All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%)
Alanine aminotransferase increased 11 2 4 0
Hypokalemia1 11 4 5 4
Aspartate aminotransferase increased 8 2 2 1
1Includes hypokalemia, blood potassium decreased
SOC=system organ class