gilotrif

Important safety information

Diarrhea : Diarrhea may result in dehydration and renal failure. Withhold GILOTRIF for severe and prolonged diarrhea not responsive to anti-diarrheal agents. ( 2.3 , 5.1 ) Bullous and exfoliative skin disorders : Severe bullous, blistering, and exfoliating lesions occurred in 0.2% of patients. Discontinue for life-threatening cutaneous reactions. Withhold GILOTRIF for severe and prolonged cutaneous reactions. ( 2.3 , 5.2 ) Interstitial lung disease (ILD) : Occurs in 1.6% of patients. Withhold GILOTRIF for acute onset or worsening of pulmonary symptoms. Discontinue GILOTRIF if ILD is diagnosed. ( 2.3 , 5.3 ) Hepatic toxicity : Fatal hepatic impairment occurs in 0.2% of patients. Monitor with periodic liver testing. Withhold or discontinue GILOTRIF for severe or worsening liver tests. ( 2.3 , 5.4 ) Gastrointestinal perforation : Occurs in 0.2% of patients. Permanently discontinue GILOTRIF in patients who develop gastrointestinal perforation. ( 2.3 , 5.5 ) Keratitis : Occurs in 0.7% of patients. Withhold GILOTRIF for keratitis evaluation. Withhold or discontinue GILOTRIF for confirmed ulcerative keratitis. ( 2.3 , 5.6 ) Embryo-fetal toxicity : Can cause fetal harm when administered to a pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to the fetus and to use effective contraception. ( 5.7 ) 5.1 Diarrhea Diarrhea has resulted in dehydration with or without renal impairment across the clinical experience; some cases were fatal. Grade 3-4 diarrhea occurred in 697 (16%) of the 4257 patients who received GILOTRIF across 44 clinical trials. In LUX-Lung 3, diarrhea occurred in 96% of patients treated with GILOTRIF (n=229), of which 15% were Grade 3 in severity and occurred within the first 6 weeks . Renal impairment as a consequence of diarrhea occurred in 6% of patients treated with GILOTRIF, of which 1.3% were Grade 3. In LUX-Lung 8, diarrhea occurred in 75% of patients treated with GILOTRIF (n=392), of which 10% were Grade 3 in severity and 0.8% were Grade 4 in severity . Renal impairment as a consequence of diarrhea occurred in 7% of patients treated with GILOTRIF, of which 2% were Grade 3 [see Adverse Reactions (6.1) ]. For patients who develop prolonged Grade 2 diarrhea lasting more than 48 hours or greater than or equal to Grade 3 diarrhea, withhold GILOTRIF until diarrhea resolves to Grade 1 or less and resume GILOTRIF with appropriate dose reduction [see Dosage and Administration (2.3) ]. Provide patients with an anti-diarrheal agent (e.g., loperamide) for self-administration at the onset of diarrhea and instruct patients to continue anti-diarrheal therapy until loose bowel movements cease for 12 hours. 5.2 Bullous and Exfoliative Skin Disorders Grade 3 cutaneous reactions characterized by bullous, blistering, and exfoliating skin lesions, occurred in 0.2% of the 4257 patients who received GILOTRIF across clinical trials . In LUX-Lung 3, the overall incidence of cutaneous reactions consisting of rash, erythema, and acneiform rash was 90%, and the incidence of Grade 3 cutaneous reactions was 16%. In addition, the incidence of Grade 1-3 palmar-plantar erythrodysesthesia syndrome was 7%. In LUX-Lung 8, the overall incidence of cutaneous reactions consisting of rash, erythema, and acneiform rash was 70%, and the incidence of Grade 3 cutaneous reactions was 7%. In addition, the incidence of Grade 1-3 palmar-plantar erythrodysesthesia syndrome was 1.5% [see Adverse Reactions (6.1) ] . Discontinue GILOTRIF in patients who develop life-threatening bullous, blistering, or exfoliating skin lesions . For patients who develop prolonged Grade 2 cutaneous adverse reactions lasting more than 7 days, intolerable Grade 2 cutaneous reactions, or Grade 3 cutaneous reactions, withhold GILOTRIF until the adverse reaction resolves to Grade 1 or less and resume GILOTRIF with appropriate dose reduction [see Dosage and Administration (2.3) ] . Postmarketing cases consistent with toxic epidermal necrolysis (TEN) and Stevens Johnson syndrome (SJS) have been reported in patients receiving GILOTRIF. The cases of TEN and SJS bullous skin reactions result from a distinct and separate mechanism of toxicity than the bullous skin lesions secondary to the pharmacologic action of the drug on the epidermal growth factor receptor. Discontinue GILOTRIF if TEN or SJS is suspected [see Dosage and Administration (2.3) ]. 5.3 Interstitial Lung Disease Interstitial lung disease or ILD-like adverse reactions (e.g., lung infiltration, pneumonitis, acute respiratory distress syndrome, or alveolitis allergic) occurred in 1.6% of the 4257 patients who received GILOTRIF across clinical trials; of these, 0.4% were fatal. The incidence of ILD appeared to be higher in Asian patients (2.3%; 38/1657) as compared to Whites (1.0%; 23/2241). In LUX-Lung 3, the incidence of Grade ≥3 ILD was 1.3% and resulted in death in 1% of GILOTRIF-treated patients. In LUX-Lung 8, the incidence of Grade ≥3 ILD was 0.9% and resulted in death in 0.8% of GILOTRIF-treated patients. Withhold GILOTRIF during evaluation of patients with suspected ILD and discontinue GILOTRIF in patients with confirmed ILD [see Dosage and Administration (2.3) ] . 5.4 Hepatic Toxicity In 4257 patients who received GILOTRIF across clinical trials, 9.7% had liver test abnormalities, of which 0.2% were fatal. In LUX-Lung 3, liver test abnormalities of any grade occurred in 17.5% of the patients treated with GILOTRIF, of which 3.5% had Grade 3-4 liver test abnormalities. In LUX-Lung 8, liver test abnormalities of any grade occurred in 6% of the patients treated with GILOTRIF, of which 0.2% had Grade 3-4 liver test abnormalities. Obtain periodic liver testing in patients during treatment with GILOTRIF. Withhold GILOTRIF in patients who develop worsening of liver function [see Dosage and Administration (2.3) ] . In patients who develop severe hepatic impairment while taking GILOTRIF, discontinue treatment. 5.5 Gastrointestinal Perforation Gastrointestinal perforation, including fatal cases, has occurred with GILOTRIF. Gastrointestinal perforation has been reported in 0.2% of patients treated with GILOTRIF among 3213 patients across 17 randomized controlled clinical trials. Patients receiving concomitant corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs) or anti-angiogenic agents, or patients with increasing age or who have an underlying history of gastrointestinal ulceration, underlying diverticular disease or bowel metastases may be at increased risk of perforation. Permanently discontinue GILOTRIF in patients who develop gastrointestinal perforation [see Dosage and Administration (2.3) ] . 5.6 Keratitis Keratitis, characterized as acute or worsening eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain, and/or red eye occurred in 0.7% of patients treated with GILOTRIF among 4257 patients across clinical trials, of which 0.05% of patients experienced Grade 3 keratitis. Keratitis was reported in 2.2% patients in LUX-Lung 3, with Grade 3 in 0.4%. In LUX-Lung 8, keratitis was reported in 0.3% patients; there were no patients with ≥Grade 3 keratitis. Withhold GILOTRIF during evaluation of patients with suspected keratitis, and if diagnosis of ulcerative keratitis is confirmed, interrupt or discontinue GILOTRIF [see Dosage and Administration (2.3) ] . If keratitis is diagnosed, the benefits and risks of continuing treatment should be carefully considered. GILOTRIF should be used with caution in patients with a history of keratitis, ulcerative keratitis, or severe dry eye [see Adverse Reactions (6.1) ] . Contact lens use is also a risk factor for keratitis and ulceration. 5.7 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, GILOTRIF can cause fetal harm when administered to a pregnant woman. Administration of afatinib to pregnant rabbits during organogenesis at exposures approximately 0.2 times the exposure in humans at the recommended…