Gilotrif

EGFR Mutation-Positive, Metastatic Non-Small Cell Lung Cancer

GILOTRIF is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have non-resistant epidermal growth factor receptor (EGFR) mutations as detected by an FDA-approved test [see Dosage and Administration (2.1), Clinical Pharmacology (12.1), Clinical Studies (14.1)].

 Previously Treated, Metastatic Squamous NSCLC

GILOTRIF is indicated for the treatment of patients with metastatic squamous NSCLC progressing after platinum-based chemotherapy.

 Patient Selection for Non-Resistant EGFR Mutation-Positive Metastatic NSCLC

Select patients for first-line treatment of metastatic NSCLC with GILOTRIF based on the presence of non-resistant EGFR mutations in tumor specimens [see Clinical Pharmacology (12.1), Clinical Studies (14.1)]. Information on FDA-approved tests for the detection of EGFR mutations in NSCLC is available at: http://www.fda.gov/CompanionDiagnostics.

 Recommended Dosage

The recommended dosage of GILOTRIF is 40 mg orally once daily until disease progression or no longer tolerated by the patient.

Take GILOTRIF at least 1 hour before or 2 hours after a meal.

Do not take a missed dose within 12 hours of the next dose.

 Dosage Modifications for Adverse Reactions

Withhold GILOTRIF for:

• Grade* 3 or higher adverse reactions
• Diarrhea of Grade 2 persisting for 2 or more consecutive days while taking anti-diarrheal medication [see Warnings and Precautions (5.1)]
• Cutaneous reactions of Grade 2 that are prolonged (lasting more than 7 days) or intolerable [see Warnings and Precautions (5.2)]

* National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), v 3.0

Resume treatment when the adverse reaction fully resolves, returns to baseline, or improves to Grade 1. Reinstitute GILOTRIF at a reduced dose, i.e., 10 mg per day less than the dose at which the adverse reaction occurred.

Permanently discontinue GILOTRIF for:

• Life-threatening bullous, blistering, or exfoliating skin lesions [see Warnings and Precautions (5.2)]
• Confirmed interstitial lung disease (ILD) [see Warnings and Precautions (5.3)]
• Severe drug-induced hepatic impairment [see Warnings and Precautions (5.4)]
• Gastrointestinal perforation [see Warnings and Precautions (5.5)]
• Persistent ulcerative keratitis [see Warnings and Precautions (5.6)]
• Symptomatic left ventricular dysfunction [see Adverse Reactions (6.1)]
• Severe or intolerable adverse reaction occurring at a dose of 20 mg per day

 Dosage Modification for Pre-Existing Severe Renal Impairment

The recommended dosage of GILOTRIF in patients with pre-existing severe renal impairment (estimated glomerular filtration rate [eGFR*] 15 to 29 mL/min /1.73 m2) is 30 mg orally once daily [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

* Use the Modification of Diet in Renal Disease [MDRD] formula to estimate eGFR.

 Dosage Modifications for Drug Interactions

Pregnancy

Lactation

Females and Males of Reproductive Potential

Pediatric Use

Safety and effectiveness of GILOTRIF in pediatric patients have not been established.

The safety and efficacy of afatinib were assessed, but not established, in a single-arm, open-label, multicenter trial [NCT02372006] which included 37 pediatric patients 2 to <17 years of age with recurrent/refractory solid tumors with known ErbB pathway deregulation who received 80% of the adult dose per body surface area. No new safety signals were observed in pediatric patients in this trial. In these 37 patients, the pharmacokinetic parameters were within range of values in adults.

Geriatric Use

LUX-Lung 3 did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

In LUX-Lung 8, 53% of the 398 patients randomized to receive afatinib were 65 years of age or older and 11% were 75 years or older. In an exploratory subgroup analysis of LUX-Lung 8, the hazard ratio for overall survival (OS) in patients less than 65 years old was 0.68 (95% CI: 0.55, 0.85) and in patients 65 years or older was 0.95 (95% CI: 0.76, 1.19). No overall differences in safety were observed between patients 65 years and older and younger patients.

 Renal Impairment

Patients with severe renal impairment have a higher exposure to afatinib than patients with normal renal function. Administer GILOTRIF at a starting dose of 30 mg once daily in patients with severe renal impairment (eGFR 15 to 29 mL/min /1.73 m2 as determined by Modification of Diet in Renal Disease formula) [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)]. Adjustments to the starting dose of GILOTRIF are not necessary in patients with mild or moderate renal impairment (eGFR 30 to 89 mL/min /1.73 m2). GILOTRIF has not been studied in patients with eGFR <15 mL/min/1.73 m2 or on dialysis.

 Hepatic Impairment

GILOTRIF has not been studied in patients with severe (Child Pugh C) hepatic impairment. Adjustments to the starting dose of GILOTRIF are not necessary in patients with mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment [see Clinical Pharmacology (12.3)]. Closely monitor patients with severe hepatic impairment and adjust GILOTRIF dose if not tolerated.

 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.

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)].

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)].

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.

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)].

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.

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 dose of 40 mg daily resulted in embryotoxicity and, in rabbits showing maternal toxicity, increased abortions at late gestational stages. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for at least 2 weeks after the last dose of GILOTRIF [see Use in Specific Populations (8.1, 8.3)].