May 28, 2016
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Gilotrif

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Gilotrif

Side Effects
Interactions

SIDE EFFECTS

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

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 data in the WARNINGS AND PRECAUTIONS section reflect exposure to GILOTRIF for clinically significant adverse reactions in 4257 patients enrolled in Studies 1 (n=229) and 2 (n=392), and 3636 patients with cancer enrolled in 42 studies of GILOTRIF administered alone or in combination with other anti-neoplastic drugs at GILOTRIF doses ranging from 10-70 mg daily or at doses 10-160 mg in other regimens. The mean exposure was 5.5 months. The population included patients with various cancers, the most common of which were NSCLC, breast, colorectal, brain, and head and neck.

The data described below reflect exposure to GILOTRIF as a single agent in Study 1, a randomized, active-controlled trial conducted in patients with EGFR mutation-positive, metastatic NSCLC, and in Study 2, a randomized, active-controlled trial in patients with metastatic squamous NSCLC progressing after platinum-based chemotherapy.

EGFR Mutation-Positive, Metastatic NSCLC

The data in Tables 1 and 2 below reflect the exposure of 229 EGFR-tyrosine kinase inhibitor-nave, 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/m followed after 30 minutes by cisplatin 75 mg/m every three weeks for a maximum of six treatment courses.

The median exposure was 11 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).

Tables 1 and 2 summarize common adverse reactions and laboratory abnormalities in Study 1.

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

Adverse Reaction GILOTRIF
n=229
Pemetrexed/Cisplatin
n=111
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/acneiform dermatitis2 90 16 11 0
  Pruritus 21 0 1 0
  Dry skin 31 0 2 0
Infections
  Paronychia3 58 11 0 0
  Cystitis 13 1 5 0
Respiratory, thoracic and mediastinal disorders
  Epistaxis 17 0 2 1
  Rhinorrhea 11 0 6 0
Investigations
  Weight decreased 17 1 14 1
General disorders and administration site conditions
  Pyrexia 12 0 6 0
Eye disorders
  Conjunctivitis 11 0 3 0
*NCI CTCAE v 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 acne, acne pustular, dermatitis, acneiform dermatitis, dermatosis, drug eruption, erythema, exfoliative rash, folliculitis, rash, rash erythematous, rash follicular, rash generalized, rash macular, rash maculo-papular, rash pruritic, rash pustular, skin disorder, skin erosion, skin exfoliation, skin fissures, skin lesion, skin reaction, skin toxicity, skin ulcer
3Includes paronychia, nail infection, nail bed infection

Other clinically important adverse reactions observed in patients treated with GILOTRIF but that occurred at a higher incidence in pemetrexed/cisplatin-treated patients and not listed elsewhere in section 6 include: decreased appetite (29% Grade 1-4, 4% Grade 3), nausea (25% Grade 1-4, 4% Grade 3), and vomiting (23% Grade 1-4, 4% Grade 3).

Table 2 : Laboratory Abnormalities Occurring in ≥ 10% of GILOTRIF Arm and at ≥ 2% Higher Incidence than in Chemotherapy Arm in Study 1*

Laboratory Abnormality GILOTRIF
n=229
Pemetrexed/Cisplatin
n=111
All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%)
Increased alanine aminotransferase (ALT) 54 2 27 1
Increased alkaline phosphate 51 3 46 1
Decreased creatinine clearance 49 2 47 1
Increased aspartate aminotransferase (AST) 46 3 22 1
Decreased lymphocytes 38 9 32 14
Decreased potassium 30 8 11 3
Increased bilirubin 16 1 8 0
*NCI CTCAE v 3.0

Previously Treated, Metastatic Squamous NSCLC

The safety of GILOTRIF was evaluated in 392 GILOTRIF-treated patients with metastatic squamous NSCLC enrolled in a randomized, multicenter, open-label trial (Study 2). Patients were required to have received at least four cycles of platinum-based chemotherapy, ECOG Performance Status (PS) 0 or 1, and normal left ventricular ejection fraction (LVEF). Patients received GILOTRIF 40 mg once daily (n=392) or erlotinib 150 mg once daily (n=395). Treatment continued until documented disease progression or intolerance to the therapy.

Among the 392 GILOTRIF-treated patients, the median age was 65 years, 53% were 65 years of age or older, 84% were male, 72% were White, 25% were Asian, ECOG PS 0 (32%) or 1 (68%). The median exposure was 2.1 months for patients treated with GILOTRIF, 15% were exposed for at least 6 months, and 5% were exposed for at least 12 months.

Serious adverse reactions occurred in 44% of patients treated with GILOTRIF. The most frequent serious adverse reactions in patients treated with GILOTRIF were pneumonia (6.6%), diarrhea (4.6%), and dehydration and dyspnea (3.1% each). Fatal adverse reactions in GILOTRIF-treated patients included ILD (0.5%), pneumonia (0.3%), respiratory failure (0.3%), acute renal failure (0.3%), and general physical health deterioration (0.3%).

Dose reductions due to adverse reactions were required in 27% of GILOTRIF-treated patients and discontinuation of GILOTRIF for adverse reactions was required for 20%. The most frequent adverse reactions that led to dose reduction in the patients treated with GILOTRIF were diarrhea (15%), rash/acne (5.9%), and stomatitis (3.1%). The most frequent adverse reactions that led to discontinuation in GILOTRIF-treated patients were diarrhea (4.1%) and rash/acne (2.6%). Tables 3 and 4 summarize common adverse reactions and laboratory abnormalities in Study 2.

Table 3 : Adverse Reactions Reported in ≥ 10% of GILOTRIF-Treated Patients in Study 2*

Adverse Reaction GILOTRIF
n=392
Erlotinib
n=395
All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%)
Gastrointestinal disorders
  Diarrhea 75 11 41 3
  Stomatitis1 30 4 11 1
  Nausea 21 2 16 1
  Vomiting 13 1 10 1
Skin and subcutaneous tissue disorders
  Rash/acneiform dermatitis2 70 7 70 11
  Pruritus 10 0 13 0
Infections
  Paronychia3 11 1 5 0
Metabolism and nutrition disorders
  Decreased appetite 25 3 26 2
*NCI CTCAE v 3.0
1Includes stomatitis, aphthous stomatitis, mucosal inflammation, mouth ulceration, oral mucosa erosion, mucosal erosion, mucosal ulceration
2Includes acne, dermatitis, acneiform dermatitis, eczema, erythema, exfoliative rash, folliculitis, rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, rash pustular, skin exfoliation, skin fissures, skin lesion, skin reaction, skin toxicity, skin ulcer
3Includes paronychia, nail infection, nail bed infection

Table 4 : Laboratory Abnormalities Occurring in ≥ 10% of GILOTRIF Arm and at ≥ 2% Higher Incidence than in Erlotinib Arm in Study 2*

Laboratory Abnormality GILOTRIF
n=392
Erlotinib
n=395
All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%)
Increased alkaline phosphate 34 2 31 0
Decreased white blood cell count 12 1 8 1
Decreased potassium 11 1 8 1
*NCI CTCAE v 3.0

Other clinically important laboratory abnormalities observed in patients treated with GILOTRIF that are not listed in Table 4 are: increased alanine aminotransferase (10% Grade 1-4; 1% Grade 3-4), increased aspartate aminotransferase (7% Grade 1-4; 1% Grade 3-4), and increased bilirubin (3% Grade 1-4; 0 Grade 3-4).

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of GILOTRIF. 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.

Read the Gilotrif (afatinib tablets, for oral use) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

Effect Of P-glycoprotein (P-gp) Inhibitors And Inducers

Concomitant taking of P-gp inhibitors (including but not limited to ritonavir, cyclosporine A, ketoconazole, itraconazole, erythromycin, verapamil, quinidine, tacrolimus, nelfinavir, saquinavir, and amiodarone) with GILOTRIF can increase exposure to afatinib [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].

Concomitant taking of P-gp inducers (including but not limited to rifampicin, carbamazepine, phenytoin, phenobarbital, and St. John's wort) with GILOTRIF can decrease exposure to afatinib [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 5/9/2016

Side Effects
Interactions

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