Gilotrif

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 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)].

  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)].
  )
  
  
  Limitations of Use
  : Safety and efficacy of GILOTRIF were not established in patients whose tumors have resistant EGFR mutations (
  1.1 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)].

  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)].
  )
• Treatment of patients with metastatic, squamous NSCLC progressing after platinum-based chemotherapy (
  1.2 Previously Treated, Metastatic Squamous NSCLC

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

  .
  )

• Recommended dosage
  : 40 mg orally once daily (
  2.2 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.
  )
• Renal impairment
  : 30 mg orally once daily in patients with severe renal impairment (
  2.4 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.
  ,
  8.6 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 m²as 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 m²or on dialysis.
  ,
  12.3 Pharmacokinetics

  Absorption

  Following oral administration of GILOTRIF tablets, time to peak afatinib plasma concentrations (T_max) is 2 to 5 hours. Maximum concentration (C_max) and area under the concentration-time curve from time zero to infinity (AUC_0-INF) values increased slightly more than dose proportional in the range of 20 to 50 mg. The geometric mean relative bioavailability of 20 mg GILOTRIF tablets was 92% as compared to an oral solution. Steady-state plasma concentrations are achieved within 8 days of repeat dosing of GILOTRIF resulting in an accumulation of 2.8-fold for AUC and 2.1-fold for C_max.

  Effect of Food

  A high-fat meal decreased C_maxby 50% and AUC_0-INFby 39% relative to the fasted condition

  [see Dosage and Administration (2.2)]

  .

  Distribution

  In vitro

  binding of afatinib to human plasma proteins is approximately 95%.

  Elimination

  The elimination half-life of afatinib is 37 hours after repeat dosing in cancer patients.

  Metabolism

  Covalent adducts to proteins are the major circulating metabolites of afatinib and enzymatic metabolism of afatinib is minimal. The metabolites formed by CYP450-dependent reactions were approximately 9% of the total metabolic turnover in sandwich-cultured human hepatocytes. Approximately 2% of the afatinib dose was metabolized by FMO3; the CYP3A4-dependent N-demethylation was not detected.

  Excretion

  In humans, excretion of afatinib is primarily via the feces (85%) with 4% recovered in the urine following a single oral dose of [¹⁴C]-labeled afatinib solution. The parent compound accounted for 88% of the recovered dose.

  Specific Populations

  Based on the population pharmacokinetic analysis, weight, gender, age, and race do not have a clinically important effect on exposure of afatinib.

  Patients with Renal Impairment

  A pharmacokinetic study was conducted in 14 subjects with normal (eGFR ≥90 mL/min/1.73 m²) renal function, 8 subjects with moderate (eGFR 30 to 59 mL/min/1.73 m²) and 8 subjects with severe (eGFR 15 to 29 mL/min/1.73 m²) renal impairment. All subjects received a single 40 mg oral dose of GILOTRIF. The geometric mean AUC_INFfor afatinib was 50% higher in subjects with severe renal impairment and was 22% higher in subjects with moderate renal impairment as compared to subjects with normal renal function. Geometric mean C_maxwas 22% higher in subjects with severe renal impairment and was comparable in subjects with moderate renal impairment to subjects with normal renal function

  [see Dosage and Administration (2.4), Use in Specific Populations (8.6)]

  . GILOTRIF has not been studied in patients with eGFR <15 mL/min/1.73 m²or on dialysis.

  Patients with Hepatic Impairment

  Mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment had no influence on the afatinib exposure following a single dose of GILOTRIF. Subjects with severe (Child Pugh C) hepatic impairment have not been studied

  [see Use in Specific Populations (8.7)]

  .

  Drug Interactions Studies

  Clincial Studies

  Effect of P-gp Inhibitors and Inducers on Afatinib:

  The effect of ritonavir dosing time relative to a single oral dose of GILOTRIF was evaluated in healthy subjects taking 40 mg of GILOTRIF alone as compared to those after ritonavir (200 mg twice daily for 3 days) co-administration at 6 hours after GILOTRIF administration. The relative bioavailability for AUC_0-INFand C_maxof afatinib was 119% and 104% when co-administered with ritonavir, and 111% and 105% when ritonavir was administered 6 hours after taking GILOTRIF. In another study, when ritonavir (200 mg twice daily for 3 days) was administered 1 hour before a 20 mg single dose of GILOTRIF, exposure to afatinib increased by 48% for AUC_0-INFand 39% for C_max

  [see Drug Interactions (7)].

  Pre-treatment with a potent inducer of P-gp, rifampicin (600 mg once daily for 7 days) decreased the plasma exposure to afatinib by 34% (AUC_0-INF) and 22% (C_max)

  [see Drug Interactions (7)]

  .

  In Vitro Studies

  Effect of Afatinib on P-gp:

  Based on

  in vitro

  data, afatinib is an inhibitor of P-gp.

  Interaction of Afatinib with BCRP:

  Based on

  in vitro

  data, afatinib is a substrate and an inhibitor of the transporter BCRP.

  Effect of Afatinib on CYP450 Enzymes:

  Afatinib is not an inhibitor or an inducer of CYP450 enzymes (CYP1A2, 2B6, 2C8, 2C9, 2C19, and 3A4) in cultured primary human hepatocytes.
  )
• Instruct patients to take GILOTRIF at least 1 hour before or 2 hours after a meal (
  2.2 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.
  )

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.

• Diarrhea
  : Diarrhea may result in dehydration and renal failure. Withhold GILOTRIF for severe and prolonged diarrhea not responsive to anti-diarrheal agents. (
  2.3 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
  ,
  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.
  )
• 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 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
  ,
  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)].
  )
• 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 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
  ,
  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)]

  .
  )
• 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 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
  ,
  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.
  )
• Gastrointestinal perforation
  : Occurs in 0.2% of patients. Permanently discontinue GILOTRIF in patients who develop gastrointestinal perforation. (
  2.3 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
  ,
  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)]

  .
  )
• Keratitis
  : Occurs in 0.7% of patients. Withhold GILOTRIF for keratitis evaluation. Withhold or discontinue GILOTRIF for confirmed ulcerative keratitis. (
  2.3 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
  ,
  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.
  )
• 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 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)].
  )