These Highlights Do Not Include All The Information Needed To Use Gilotrif Safely And Effectively. See Full Prescribing Information For Gilotrif.

Limitations of Use: The safety and efficacy of GILOTRIF have not been established in patients whose tumors have resistant EGFR mutations [see Clinical Studies (14.1)].

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Dispense medication in the original container to protect from exposure to high humidity and light.

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.

Overdose was reported in 2 healthy adolescents each of whom ingested 360 mg of GILOTRIF (as part of a mixed-drug ingestion) resulting in nausea, vomiting, asthenia, dizziness, headache, abdominal pain, and elevated amylase [<1.5 times upper limit of normal (ULN)]. Both subjects recovered.

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.

GILOTRIF tablets contain afatinib, a tyrosine kinase inhibitor which is a 4-anilinoquinazoline. Afatinib is presented as the dimaleate salt, with the chemical name 2-butenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-,(2E)-, (2Z)-2-butenedioate (1:2). Its structural formula is:

Afatinib dimaleate is a white to brownish yellow powder, water soluble and hygroscopic, with an empirical formula of C₃₂H₃₃ClFN₅O₁₁, and a molecular weight of 718.1 g/mol.

GILOTRIF tablets for oral administration are available in 40 mg, 30 mg, or 20 mg of afatinib (equivalent to 59.12 mg, 44.34 mg, or 29.56 mg afatinib dimaleate, respectively). The inactive ingredients of GILOTRIF are the following: Tablet Core: lactose monohydrate, microcrystalline cellulose, crospovidone, colloidal silicon dioxide, magnesium stearate and Coating: hypromellose, polyethylene glycol, titanium dioxide, talc, polysorbate 80, FD&C Blue No. 2 (40 mg and 30 mg tablets only).

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.

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.

None.

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Diarrhea [see Warnings and Precautions (5.1)]
• Bullous and Exfoliative Skin Disorders [see Warnings and Precautions (5.2)]
• Interstitial Lung Disease [see Warnings and Precautions (5.3)]
• Hepatic Toxicity [see Warnings and Precautions (5.4)]
• Gastrointestinal Perforation [see Warnings and Precautions (5.5)]
• Keratitis [see Warnings and Precautions (5.6)]

• P-glycoprotein (P-gp) Inhibitors: Co-administration of P-gp inhibitors can increase afatinib exposure. Reduce GILOTRIF by 10 mg per day if not tolerated. (2.5, 7)
• P-gp Inducers: Co-administration of chronic P-gp inducers orally can decrease afatinib exposure. Increase GILOTRIF by 10 mg per day as tolerated. (2.5, 7)

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.

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.

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.

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.

GILOTRIF is a kinase inhibitor indicated for:

• 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 (1.1)
  
  Limitations of Use: Safety and efficacy of GILOTRIF were not established in patients whose tumors have resistant EGFR mutations (1.1)
• Treatment of patients with metastatic, squamous NSCLC progressing after platinum-based chemotherapy (1.2)

Afatinib covalently binds to the kinase domains of EGFR (ErbB1), HER2 (ErbB2), and HER4 (ErbB4) and irreversibly inhibits tyrosine kinase autophosphorylation, resulting in downregulation of ErbB signaling. Certain mutations in EGFR, including non-resistant mutations in its kinase domain, can result in increased autophosphorylation of the receptor, leading to receptor activation, sometimes in the absence of ligand binding, and can support cell proliferation in NSCLC. Non-resistant mutations are defined as those occurring in exons constituting the kinase domain of EGFR that lead to increased receptor activation and where efficacy is predicted by 1) clinically meaningful tumor shrinkage with the recommended dose of afatinib and/or 2) inhibition of cellular proliferation or EGFR tyrosine kinase phosphorylation at concentrations of afatinib sustainable at the recommended dosage according to validated methods. The most commonly found of these mutations are exon 21 L858R substitutions and exon 19 deletions.

Afatinib demonstrated inhibition of autophosphorylation and/or in vitro proliferation of cell lines expressing wild-type EGFR and in those expressing selected EGFR exon 19 deletion mutations, exon 21 L858R mutations, or other less common non-resistant mutations, at afatinib concentrations achieved in patients. In addition, afatinib inhibited in vitro proliferation of cell lines overexpressing HER2.

Treatment with afatinib resulted in inhibition of tumor growth in nude mice implanted with tumors either overexpressing wild type EGFR or HER2 or in an EGFR L858R/T790M double mutant model.

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)].

• 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)

• Recommended dosage: 40 mg orally once daily (2.2)
• Renal impairment: 30 mg orally once daily in patients with severe renal impairment (2.4, 8.6, 12.3)
• Instruct patients to take GILOTRIF at least 1 hour before or 2 hours after a meal (2.2)

GILOTRIF is available as:

• 40 mg tablets: light blue, film-coated, round, biconvex, bevel-edged tablets debossed with "T40" on one side and the Boehringer Ingelheim company symbol on the other side.
• 30 mg tablets: dark blue, film-coated, round, biconvex, bevel-edged tablets debossed with "T30" on one side and the Boehringer Ingelheim company symbol on the other side.
• 20 mg tablets: white to slightly yellowish, film-coated, round, biconvex, bevel-edged tablets debossed with "T20" on one side and the Boehringer Ingelheim company symbol on the other side.

The following adverse reactions have been identified during postapproval 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.

• Pancreatitis
• Toxic epidermal necrolysis/Stevens Johnson syndrome

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)].

Lactation: Advise women not to breastfeed (8.2)

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 LUX-Lung 3 (n=229) and LUX-Lung 8 (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 LUX-Lung 3, a randomized, active-controlled trial conducted in patients with EGFR mutation-positive, metastatic NSCLC, and in LUX-Lung 8, a randomized, active-controlled trial in patients with metastatic squamous NSCLC progressing after platinum-based chemotherapy.

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)].

Advise the patient to read the FDA-approved patient labeling (Patient Information).

GILOTRIF tablets are available as follows:

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)].

The efficacy of GILOTRIF for the first-line treatment of patients with EGFR mutation-positive, metastatic [Stage IV and Stage IIIb with pleural and/or pericardial effusion as classified by the American Joint Commission on Cancer (AJCC, 6th edition)] NSCLC was established in a randomized, multicenter, open-label trial (LUX-Lung 3 [NCT00949650]). Patients were randomized (2:1) to receive GILOTRIF 40 mg orally once daily (n=230) or intravenous pemetrexed (500 mg/m²) plus cisplatin (75 mg/m²) once every 21 days for up to 6 cycles (n=115). Randomization was stratified according to EGFR mutation category (exon 19 deletion vs exon 21 L858R vs other) and race (Asian vs non-Asian). The major efficacy outcome was progression-free survival (PFS) as assessed by an independent review committee (IRC). Other efficacy outcomes included overall response rate (ORR) and OS. EGFR mutation status was prospectively determined for screening and enrollment of patients by a clinical trial assay (CTA). Tumor samples from 264 patients (178 randomized to GILOTRIF and 86 patients randomized to chemotherapy) were tested retrospectively by the companion diagnostic therascreen ^® EGFR RGQ PCR Kit, which is FDA-approved for selection of patients for GILOTRIF treatment.

Among the patients randomized, 65% were female, median age was 61 years, baseline ECOG performance status (PS) was 0 (39%) or 1 (61%), 26% were White and 72% were Asian. The majority of the patients had a tumor sample with an EGFR mutation categorized by the CTA as either exon 19 deletion (49%) or exon 21 L858R substitution (40%), while the remaining 11% had other mutations.

A statistically significant improvement in PFS as determined by the IRC was demonstrated for patients randomized to GILOTRIF compared with those randomized to chemotherapy. See Table 5 and Figure 1. There was no statistically significant difference for OS between the treatment arms at the final pre-planned analysis.

Figure 1 Kaplan-Meier Curve for PFS by Independent Review by Treatment Group in LUX-Lung 3

Pre-specified exploratory subgroup analyses were conducted according to the stratification factor of EGFR mutation category. See Figure 2 and text below Figure 2.

Figure 2 Forest Plots of PFS and OS by EGFR Mutation Subgroups in LUX-Lung 3

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

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

The efficacy and safety of GILOTRIF were demonstrated in a randomized, multicenter, open-label, active-controlled study (LUX-Lung 8 [NCT01523587]). Patients were required to have histologically documented, metastatic squamous NSCLC and have experienced disease progression following an adequate course (≥4 cycles) of a platinum-based doublet chemotherapy regimen. Patients were randomized (1:1) to receive GILOTRIF 40 mg or erlotinib 150 mg orally once daily until progression. Randomization was stratified by region (Eastern Asia vs other). The major efficacy outcome measure was PFS as assessed by an IRC using RECIST v 1.1. Additional efficacy outcome measures were OS and ORR as assessed by IRC.

Baseline patient demographics of the 795 patients were: median age 64 years (range: 35 to 88); 73% White; 24% Asian; 84% male; 33% ECOG PS 0 and 67% ECOG PS 1; and 95% current or former smokers. With regard to tumor characteristics, 96% had squamous cell histology and 3.5% had mixed cell histology. All patients received platinum-based doublet therapy.

The study demonstrated a statistically significant improvement in PFS and OS for patients randomized to GILOTRIF as compared with erlotinib (see Table 7 and Figure 3).

Figure 3 Kaplan-Meier Curves of Overall Survival in LUX-Lung 8

NDC 0597-0141-30

GILOTRIF^®

(afatinib tablets)

20 mg*

Attention: Dispense and Store

Medication in the Original Container

to Protect from Light and Humidity.

Recommended Dosage: See Prescribing

Information.

30 tablets

Boehringer

Ingelheim

Rx only

NDC 0597-0137-30

GILOTRIF^®

(afatinib tablets)

30 mg*

Attention: Dispense and Store

Medication in the Original Container

to Protect from Light and Humidity.

Recommended Dosage: See Prescribing

Information.

30 tablets

Boehringer

Ingelheim

Rx only

NDC 0597-0138-30

GILOTRIF^®

(afatinib tablets)

40 mg*

Attention: Dispense and Store

Medication in the Original Container

to Protect from Light and Humidity.

Recommended Dosage:

See Prescribing Information.

30 tablets

Boehringer

Ingelheim

Rx only

Carcinogenicity studies have not been conducted with afatinib.

A marginal response to afatinib was observed in a single tester strain of a bacterial (Ames) mutagenicity assay. No mutagenic or genotoxic potential was identified in an in vitro chromosomal aberration test at non-cytotoxic concentrations as well as in the in vivo bone marrow micronucleus assay, the in vivo Comet assay, and an in vivo 4-week oral mutation study in the Muta^™ Mouse.

In a dedicated fertility study, male and female rats received afatinib daily by oral administration at doses of 4, 6, or 8 mg/kg. In males at doses of 6 mg/kg (approximately equal to the exposure by AUC in patients at the recommended human dose of 40 mg daily) or greater, there was an increase in the incidence of low or no sperm count, though overall fertility was not affected; decreases in sperm count were supported by findings of increased apoptosis in the testes and atrophy in the seminal vesicles and the prostate in general toxicology studies. In females at the high dose of 8 mg/kg (approximately 0.63 times the exposure by AUC in patients at the recommended human dose of 40 mg daily), there was a mild decrease in the number of corpora lutea along with a mild increase in post-implantation loss due to early resorptions. In a 4-week general toxicology study, female rats had decreases in ovarian weights at all dose levels; organ weight had not fully recovered by the end of a 2-week recovery period.

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.

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)].

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.

Limitations of Use: The safety and efficacy of GILOTRIF have not been established in patients whose tumors have resistant EGFR mutations [see Clinical Studies (14.1)].

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Dispense medication in the original container to protect from exposure to high humidity and light.

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.

Overdose was reported in 2 healthy adolescents each of whom ingested 360 mg of GILOTRIF (as part of a mixed-drug ingestion) resulting in nausea, vomiting, asthenia, dizziness, headache, abdominal pain, and elevated amylase [<1.5 times upper limit of normal (ULN)]. Both subjects recovered.

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.

GILOTRIF tablets contain afatinib, a tyrosine kinase inhibitor which is a 4-anilinoquinazoline. Afatinib is presented as the dimaleate salt, with the chemical name 2-butenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-,(2E)-, (2Z)-2-butenedioate (1:2). Its structural formula is:

Afatinib dimaleate is a white to brownish yellow powder, water soluble and hygroscopic, with an empirical formula of C₃₂H₃₃ClFN₅O₁₁, and a molecular weight of 718.1 g/mol.

GILOTRIF tablets for oral administration are available in 40 mg, 30 mg, or 20 mg of afatinib (equivalent to 59.12 mg, 44.34 mg, or 29.56 mg afatinib dimaleate, respectively). The inactive ingredients of GILOTRIF are the following: Tablet Core: lactose monohydrate, microcrystalline cellulose, crospovidone, colloidal silicon dioxide, magnesium stearate and Coating: hypromellose, polyethylene glycol, titanium dioxide, talc, polysorbate 80, FD&C Blue No. 2 (40 mg and 30 mg tablets only).

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.

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.

None.

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Diarrhea [see Warnings and Precautions (5.1)]
• Bullous and Exfoliative Skin Disorders [see Warnings and Precautions (5.2)]
• Interstitial Lung Disease [see Warnings and Precautions (5.3)]
• Hepatic Toxicity [see Warnings and Precautions (5.4)]
• Gastrointestinal Perforation [see Warnings and Precautions (5.5)]
• Keratitis [see Warnings and Precautions (5.6)]

• P-glycoprotein (P-gp) Inhibitors: Co-administration of P-gp inhibitors can increase afatinib exposure. Reduce GILOTRIF by 10 mg per day if not tolerated. (2.5, 7)
• P-gp Inducers: Co-administration of chronic P-gp inducers orally can decrease afatinib exposure. Increase GILOTRIF by 10 mg per day as tolerated. (2.5, 7)

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.

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.

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.

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.

GILOTRIF is a kinase inhibitor indicated for:

• 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 (1.1)
  
  Limitations of Use: Safety and efficacy of GILOTRIF were not established in patients whose tumors have resistant EGFR mutations (1.1)
• Treatment of patients with metastatic, squamous NSCLC progressing after platinum-based chemotherapy (1.2)

Afatinib covalently binds to the kinase domains of EGFR (ErbB1), HER2 (ErbB2), and HER4 (ErbB4) and irreversibly inhibits tyrosine kinase autophosphorylation, resulting in downregulation of ErbB signaling. Certain mutations in EGFR, including non-resistant mutations in its kinase domain, can result in increased autophosphorylation of the receptor, leading to receptor activation, sometimes in the absence of ligand binding, and can support cell proliferation in NSCLC. Non-resistant mutations are defined as those occurring in exons constituting the kinase domain of EGFR that lead to increased receptor activation and where efficacy is predicted by 1) clinically meaningful tumor shrinkage with the recommended dose of afatinib and/or 2) inhibition of cellular proliferation or EGFR tyrosine kinase phosphorylation at concentrations of afatinib sustainable at the recommended dosage according to validated methods. The most commonly found of these mutations are exon 21 L858R substitutions and exon 19 deletions.

Afatinib demonstrated inhibition of autophosphorylation and/or in vitro proliferation of cell lines expressing wild-type EGFR and in those expressing selected EGFR exon 19 deletion mutations, exon 21 L858R mutations, or other less common non-resistant mutations, at afatinib concentrations achieved in patients. In addition, afatinib inhibited in vitro proliferation of cell lines overexpressing HER2.

Treatment with afatinib resulted in inhibition of tumor growth in nude mice implanted with tumors either overexpressing wild type EGFR or HER2 or in an EGFR L858R/T790M double mutant model.

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)].

• 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)

• Recommended dosage: 40 mg orally once daily (2.2)
• Renal impairment: 30 mg orally once daily in patients with severe renal impairment (2.4, 8.6, 12.3)
• Instruct patients to take GILOTRIF at least 1 hour before or 2 hours after a meal (2.2)

GILOTRIF is available as:

• 40 mg tablets: light blue, film-coated, round, biconvex, bevel-edged tablets debossed with "T40" on one side and the Boehringer Ingelheim company symbol on the other side.
• 30 mg tablets: dark blue, film-coated, round, biconvex, bevel-edged tablets debossed with "T30" on one side and the Boehringer Ingelheim company symbol on the other side.
• 20 mg tablets: white to slightly yellowish, film-coated, round, biconvex, bevel-edged tablets debossed with "T20" on one side and the Boehringer Ingelheim company symbol on the other side.

The following adverse reactions have been identified during postapproval 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.

• Pancreatitis
• Toxic epidermal necrolysis/Stevens Johnson syndrome

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)].

Lactation: Advise women not to breastfeed (8.2)

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 LUX-Lung 3 (n=229) and LUX-Lung 8 (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 LUX-Lung 3, a randomized, active-controlled trial conducted in patients with EGFR mutation-positive, metastatic NSCLC, and in LUX-Lung 8, a randomized, active-controlled trial in patients with metastatic squamous NSCLC progressing after platinum-based chemotherapy.

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)].

Advise the patient to read the FDA-approved patient labeling (Patient Information).

GILOTRIF tablets are available as follows:

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)].

The efficacy of GILOTRIF for the first-line treatment of patients with EGFR mutation-positive, metastatic [Stage IV and Stage IIIb with pleural and/or pericardial effusion as classified by the American Joint Commission on Cancer (AJCC, 6th edition)] NSCLC was established in a randomized, multicenter, open-label trial (LUX-Lung 3 [NCT00949650]). Patients were randomized (2:1) to receive GILOTRIF 40 mg orally once daily (n=230) or intravenous pemetrexed (500 mg/m²) plus cisplatin (75 mg/m²) once every 21 days for up to 6 cycles (n=115). Randomization was stratified according to EGFR mutation category (exon 19 deletion vs exon 21 L858R vs other) and race (Asian vs non-Asian). The major efficacy outcome was progression-free survival (PFS) as assessed by an independent review committee (IRC). Other efficacy outcomes included overall response rate (ORR) and OS. EGFR mutation status was prospectively determined for screening and enrollment of patients by a clinical trial assay (CTA). Tumor samples from 264 patients (178 randomized to GILOTRIF and 86 patients randomized to chemotherapy) were tested retrospectively by the companion diagnostic therascreen ^® EGFR RGQ PCR Kit, which is FDA-approved for selection of patients for GILOTRIF treatment.

Among the patients randomized, 65% were female, median age was 61 years, baseline ECOG performance status (PS) was 0 (39%) or 1 (61%), 26% were White and 72% were Asian. The majority of the patients had a tumor sample with an EGFR mutation categorized by the CTA as either exon 19 deletion (49%) or exon 21 L858R substitution (40%), while the remaining 11% had other mutations.

A statistically significant improvement in PFS as determined by the IRC was demonstrated for patients randomized to GILOTRIF compared with those randomized to chemotherapy. See Table 5 and Figure 1. There was no statistically significant difference for OS between the treatment arms at the final pre-planned analysis.

Figure 1 Kaplan-Meier Curve for PFS by Independent Review by Treatment Group in LUX-Lung 3

Pre-specified exploratory subgroup analyses were conducted according to the stratification factor of EGFR mutation category. See Figure 2 and text below Figure 2.

Figure 2 Forest Plots of PFS and OS by EGFR Mutation Subgroups in LUX-Lung 3

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

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

The efficacy and safety of GILOTRIF were demonstrated in a randomized, multicenter, open-label, active-controlled study (LUX-Lung 8 [NCT01523587]). Patients were required to have histologically documented, metastatic squamous NSCLC and have experienced disease progression following an adequate course (≥4 cycles) of a platinum-based doublet chemotherapy regimen. Patients were randomized (1:1) to receive GILOTRIF 40 mg or erlotinib 150 mg orally once daily until progression. Randomization was stratified by region (Eastern Asia vs other). The major efficacy outcome measure was PFS as assessed by an IRC using RECIST v 1.1. Additional efficacy outcome measures were OS and ORR as assessed by IRC.

Baseline patient demographics of the 795 patients were: median age 64 years (range: 35 to 88); 73% White; 24% Asian; 84% male; 33% ECOG PS 0 and 67% ECOG PS 1; and 95% current or former smokers. With regard to tumor characteristics, 96% had squamous cell histology and 3.5% had mixed cell histology. All patients received platinum-based doublet therapy.

The study demonstrated a statistically significant improvement in PFS and OS for patients randomized to GILOTRIF as compared with erlotinib (see Table 7 and Figure 3).

Figure 3 Kaplan-Meier Curves of Overall Survival in LUX-Lung 8

NDC 0597-0141-30

GILOTRIF^®

(afatinib tablets)

20 mg*

Attention: Dispense and Store

Medication in the Original Container

to Protect from Light and Humidity.

Recommended Dosage: See Prescribing

Information.

30 tablets

Boehringer

Ingelheim

Rx only

NDC 0597-0137-30

GILOTRIF^®

(afatinib tablets)

30 mg*

Attention: Dispense and Store

Medication in the Original Container

to Protect from Light and Humidity.

Recommended Dosage: See Prescribing

Information.

30 tablets

Boehringer

Ingelheim

Rx only

NDC 0597-0138-30

GILOTRIF^®

(afatinib tablets)

40 mg*

Attention: Dispense and Store

Medication in the Original Container

to Protect from Light and Humidity.

Recommended Dosage:

See Prescribing Information.

30 tablets

Boehringer

Ingelheim

Rx only

Carcinogenicity studies have not been conducted with afatinib.

A marginal response to afatinib was observed in a single tester strain of a bacterial (Ames) mutagenicity assay. No mutagenic or genotoxic potential was identified in an in vitro chromosomal aberration test at non-cytotoxic concentrations as well as in the in vivo bone marrow micronucleus assay, the in vivo Comet assay, and an in vivo 4-week oral mutation study in the Muta^™ Mouse.

In a dedicated fertility study, male and female rats received afatinib daily by oral administration at doses of 4, 6, or 8 mg/kg. In males at doses of 6 mg/kg (approximately equal to the exposure by AUC in patients at the recommended human dose of 40 mg daily) or greater, there was an increase in the incidence of low or no sperm count, though overall fertility was not affected; decreases in sperm count were supported by findings of increased apoptosis in the testes and atrophy in the seminal vesicles and the prostate in general toxicology studies. In females at the high dose of 8 mg/kg (approximately 0.63 times the exposure by AUC in patients at the recommended human dose of 40 mg daily), there was a mild decrease in the number of corpora lutea along with a mild increase in post-implantation loss due to early resorptions. In a 4-week general toxicology study, female rats had decreases in ovarian weights at all dose levels; organ weight had not fully recovered by the end of a 2-week recovery period.

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.

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)].

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.