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Dosing and Administration

GILOTRIF DOSING

Patient Selection1

  • Select patients for the first-line treatment of mNSCLC with GILOTRIF® (afatinib) based on the presence of non-resistant EGFR mutations in tumor specimens
  • Information on FDA-approved tests for the detection of EGFR mutations in NSCLC is available at: http://www.fda.gov/CompanionDiagnostics
  • Select patients for treatment of metastatic squamous NSCLC based on progression following platinum-based chemotherapy; follow dosing steps below
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Recommended dose1
  • The recommended dose is 40 mg orally once daily
  • The recommended dosage of GILOTRIF in patients with pre-existing severe renal impairment is 30 mg orally once daily.*
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How to take1
  • 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
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Treatment duration1
  • Treatment should be continued until disease progression or until no longer tolerated by the patient
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Multiple strengths1
  • Multiple tablet strengths are available for dose adjustment

*Severe renal impairment was considered to be an estimated glomular filtration rate (eGFR) 15 to 29 mL/min/1.73 m2.

Gilotrif 40mg tablets
GILOTRIF 40 mg tablet
Not actual size
Gilotrif 30mg tablets
GILOTRIF 30 mg tablet
Not actual size
Gilotrif 20mg tablets
GILOTRIF 20 mg tablet
Not actual size
DOSE MODIFICATION

Dose modification can be an important strategy to help manage adverse reactions1,5

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1. Initiate
  • Initiate therapy at the recommended 40-mg dose
  • The recommended dosage of GILOTRIF in patients with pre-existing severe renal impairment is 30 mg orally once daily.*
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2. Evaluate
  • Evaluate patients for adverse reactions within 2 weeks and periodically thereafter
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3. Pause
  • Pause treatment for ≥grade 3 adverse reactions†
  • Or ≥grade 2 diarrhea (prolonged)‡ cutaneous reactions (prolonged or intolerable)§ renal impairment
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4. Resume
  • Resume treatment at 10-mg less per day when adverse reaction fully resolves, returns to baseline, or improves to grade 1

Permanently discontinue GILOTRIF for: Life-threatening bullous, blistering, or exfoliating skin lesions; confirmed interstitial lung disease (ILD); severe drug-induced hepatic impairment; gastrointestinal perforation; persistent ulcerative keratitis; symptomatic left ventricular dysfunction; and severe or intolerable AR occurring at a dose of 20 mg per day.1

*Severe renal impairment was considered to be an estimated glomular filtration rate (eGFR) 15 to 29 mL/min/1.73 m2.

†National Cancer Institute Common Terminology Criteria for Adverse Events, v4.03.

‡Grade ≥2 diarrhea persisting ≥48 hours while taking antidiarrheal medication.

§Grade 2 cutaneous reactions >7 days.

QT prolongation

  • The effect of multiple doses of GILOTRIF (50 mg once daily) on the QTc interval was evaluated in an open-label, single-arm study in patients with relapsed or refractory solid tumors
  • No large changes in the mean QTc interval (ie, >20 ms) were detected in the study

Concomitant use with P-glycoprotein (P-gp) inducers

P-gp inducers (including but not limited to rifampicin, carbamazepine, phenytoin, phenobarbital, and St. John's wort) can decrease exposure to GILOTRIF

  • Increase GILOTRIF daily dose by 10 mg as tolerated. Resume the previous dose 2 to 3 days after discontinuation of the P-gp inducer

Concomitant use with P-glycoprotein (P-gp) inhibitors

P-gp inhibitors (including but not limited to ritonavir, cyclosporine A, ketoconazole, itraconazole, erythromycin, verapamil, quinidine, tacrolimus, nelfinavir, saquinavir, and amiodarone) can increase exposure to GILOTRIF

  • Reduce GILOTRIF daily dose by 10 mg if not tolerated. Resume the previous dose after discontinuation of the P-gp inhibitor as tolerated

CYP450 enzymes

  • GILOTRIF is not an inhibitor or inducer of CYP450 enzymes
LUX-LUNG 3: DOSE MODIFICATION

Dose adjustment reduced the frequency and severity of ARs in a post-hoc analysis of LUX-Lung 35

LUX-Lung 3: Over half of patients reduced their dose1,5

The most common Grade 3 ARs that led to dose reduction with GILOTRIF in the analysis were rash/acne (26.2%), diarrhea, (20.5%), paronychia (16.4%), and stomatitis (12.3%)5

57 percent icon

Among patients that dose reduced In LUX-Lung 3 due to Grade 3 ARs5

In LUX-Lung 3, 86.1% of dose adjustments occurred within the first 6 months of treatment5

Grade ≥3 ARs with dose adjustment5,a,b

chart ARs dose adjustment

ARs=adverse reactions.

aSelected based on the 4 most common treatment-related adverse reactions pre- and post-dose reduction in LUX-Lung 3.

bPost-hoc analysis included all of GILOTRIF-treated patients in LUX-Lung 3.

Safety Information from LUX-Lung 3

Adverse reactions (ARs) reported in LUX-Lung 3 in ≥10% of GILOTRIF-treated patients1

Adverse reactionGILOTRIF (n=229) Grade 3,† %Pemetrexed-cisplatin (n=111) Grade 3,† %GILOTRIF (n=229) All grades, %Pemetrexed-cisplatin (n=111) All grades, %
Gastrointestinal disorders
Diarrhea1529623
Stomatitis‡917115
Cheilitis00121
Skin and subcutaneous tissue disorders
Rash/acneiform dermatitis§1609011
Pruritus00211
Dry skin00312
Infections
Paronychia110580
Cystitis10135
Respiratory, thoracic, and mediastinal disorders
Epistaxis01172
Rhinorrhea00116
Investigations
Weight decreased111714
General disorders and administration site conditions
Pyrexia00126
Eye disorders
Conjunctivitis00113

†National Cancer Institute Common Terminology Criteria for Adverse Events, v4.03.

‡Grade ≥2 diarrhea persisting ≥48 hours while taking antidiarrheal medication.

§Grade 2 cutaneous reactions >7 days.

Other clinically important ARs observed in patients treated with GILOTRIF include decreased appetite (29%), nausea (25%), and vomiting (23%)1

Serious ARs reported in LUX-Lung 3

  • Serious ARs were reported in 29% of patients treated with GILOTRIF. The most frequent serious ARs reported in patients treated with GILOTRIF were diarrhea (6.6%), vomiting (4.8%), and dyspnea, fatigue, and hypokalemia (1.7% each). Fatal ARs in GILOTRIF-treated patients included pulmonary toxicity/ILD-like ARs (1.3%), sepsis (0.43%), and pneumonia (0.43%)

Discontinuations in LUX-Lung 3

  • Discontinuation of therapy in GILOTRIF-treated patients for ARs was 14%
  • The most frequent ARs that led to discontinuation in GILOTRIF-treated patients were diarrhea (1.3%), ILD (0.9%), and paronychia (0.9%)

PFS results were consistent among patients with or without dose adjustments, based on a post-hoc analysis of LUX-Lung 35

PFS results were consistent among patients who required dose reductions within the first 6 months and those who remained on GILOTRIF 40 mg5

  • The most frequent adverse reactions that led to dose reduction in the patients treated with GILOTRIF were diarrhea (20%), rash/acne (19%), paronychia (14%), and stomatitis (10%)1

PFS in patients with or without dose reductions within the first 6 months5,c

PFS in patients line graph

cData from intention-to-treat population, which includes both patients with common and uncommon EGFR mutations.

REALGIDO STUDY

Real-world evidence reinforces that GILOTRIF dose adjustments may reduce the frequency and severity of ARs with no apparent compromise on effectiveness4,6

  • GILOTRIF starting dose in RealGiDo: 73 patients received a starting dose other than 40 mg/day; 155 patients received recommended starting dose of 40 mg/day◊
  • Primary RealGiDo safety and efficacy outcomes: percentage of patients with adverse drug reactions by severity, time to treatment failure (time on treatment), and time to progression

Results are not intended for direct comparison with clinical trials. Differences in study designs, patient populations, definitions of safety or efficacy outcomes, as well as data collection methods, make it difficult to compare real-world studies with clinical trials.

Limitations: The main limitations of the study were its retrospective nature and potential for selection bias. Sites that had experience prescribing afatinib and managing adverse events regularly were included in the study, however, enrollment was capped at 15 patients per site.

◊Although assessed as part of a global study, not all are approved doses in the US.

RealGiDo: Safety profile in patients who received a modified GILOTRIF dose <6 months after starting on GILOTRIF 40 mg5

Overall (grade ≥3) incidences of most common ARs (n=56)

ARPre-dose modification (%)Post-dose modification (%)
Diarrhea13.71.4
Oral mucositis8.21.4
Rash acneiform9.62.7
Paronychia1.42.7

Overall incidence of ARs pre- and post-dose modification (n=91)

ARs (all grades)98.671.2

Median time to treatment failure and progression in RealGiDo4

Median time to treatment failure*

chart median TTF

Median time to progression*

chart median TTP

NE=not evaluable.

*Time to treatment failure is defined as the time from the first dose of afatinib to the last dose of afatinib. Time to progression is defined as the time from the first dose of afatinib to the earliest occurrence of documented progression or death.

RealGiDo Study: Common adverse drug reactions (>10% incidence) pre- and post-dose reduction within the first 6 months after starting on GILOTRIF 40 mg/day (n=91)4

RealGiDo study adverse reaction chart

Results are not intended for direct comparison with clinical trials. Differences in study designs, patient populations, definitions of safety or efficacy outcomes, as well as data collection methods, make it difficult to compare real-world studies with clinical trials.

Limitations: The main limitations of the study were its retrospective nature and potential for selection bias. Sites that had experience prescribing afatinib and managing adverse events regularly were included in the study, however, enrollment was capped at 15 patients per site.

Learn about RealGiDo:

A retrospective, observational study on afatinib dose adjustments in patients with EGFR M+ mNSCLC4

Learn More

ARs=adverse reactions; TTF=time to treatment failure; TTP=time to progression.

*Severe renal impairment was considered to be an estimated glomular filtration rate (eGFR) 15 to 29 mL/min/1.73 m2.

INDICATIONS AND USAGE

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.

Limitations of Use: Safety and efficacy of GILOTRIF have not been established in patients whose tumors have resistant EGFR mutations.

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

IMPORTANT SAFETY INFORMATION FOR GILOTRIF® (afatinib) TABLETS WARNINGS AND PRECAUTIONS
Diarrhea
  • GILOTRIF can cause diarrhea which may be severe and can result in dehydration with or without renal impairment. In clinical studies, some of these cases were fatal.
  • For patients who develop Grade 2 diarrhea lasting more than 48 hours or Grade 3 or greater diarrhea, withhold GILOTRIF until diarrhea resolves to Grade 1 or less, and then resume at a reduced dose.
  • 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 until loose stools cease for 12 hours.
Bullous and Exfoliative Skin Disorders
  • GILOTRIF can result in cutaneous reactions consisting of rash, erythema, and acneiform rash. In addition, palmar-plantar erythrodysesthesia syndrome was observed in clinical trials in patients taking GILOTRIF.
  • Discontinue GILOTRIF in patients who develop life-threatening bullous, blistering, or exfoliating skin lesions. For patients who develop Grade 2 cutaneous adverse reactions lasting more than 7 days, intolerable Grade 2, or Grade 3 cutaneous reactions, withhold GILOTRIF. When the adverse reaction resolves to Grade 1 or less, resume GILOTRIF with appropriate dose reduction.
  • Postmarketing cases of toxic epidermal necrolysis (TEN) and Stevens Johnson syndrome (SJS) have been reported in patients receiving GILOTRIF. Discontinue GILOTRIF if TEN or SJS is suspected.
Interstitial Lung Disease
  • Interstitial Lung Disease (ILD) or ILD-like adverse reactions (e.g., lung infiltration, pneumonitis, acute respiratory distress syndrome, or alveolitis allergic) occurred in patients receiving GILOTRIF in clinical trials. In some cases, ILD was fatal. The incidence of ILD appeared to be higher in Asian patients as compared to white patients.
  • Withhold GILOTRIF during evaluation of patients with suspected ILD, and discontinue GILOTRIF in patients with confirmed ILD.
Hepatic Toxicity
  • Hepatic toxicity as evidenced by liver function tests abnormalities has been observed in patients taking GILOTRIF. In 4257 patients who received GILOTRIF across clinical trials, 9.7% had liver test abnormalities, of which 0.2% were fatal.
  • Obtain periodic liver testing in patients during treatment with GILOTRIF. Withhold GILOTRIF in patients who develop worsening of liver function. Discontinue treatment in patients who develop severe hepatic impairment while taking GILOTRIF.
Gastrointestinal Perforation
  • Gastrointestinal (GI) perforation, including fatal cases, has occurred with GILOTRIF. GI 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 GI ulceration, underlying diverticular disease, or bowel metastases may be at an increased risk of perforation.
  • Permanently discontinue GILOTRIF in patients who develop GI perforation.
Keratitis
  • Keratitis has been reported in patients taking GILOTRIF.
  • Withhold GILOTRIF during evaluation of patients with suspected keratitis. If diagnosis of ulcerative keratitis is confirmed, interrupt or discontinue GILOTRIF. 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. Contact lens use is also a risk factor for keratitis and ulceration.
Embryo-Fetal Toxicity
  • GILOTRIF can cause fetal harm when administered to a pregnant woman. 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. Advise female patients to contact their healthcare provider with a known or suspected pregnancy.
ADVERSE REACTIONS
Adverse Reactions observed in clinical trials were as follows:
First-line treatment of EGFR mutation-positive, metastatic NSCLC
  • In GILOTRIF-treated patients (n=229) the most common adverse reactions (≥20% all grades & vs pemetrexed/cisplatin-treated patients (n=111)) were diarrhea (96% vs 23%), rash/acneiform dermatitis (90% vs 11%), stomatitis (71% vs 15%), paronychia (58% vs 0%), dry skin (31% vs 2%) and pruritus (21% vs 1%). Other clinically important adverse reactions observed in patients treated with GILOTRIF include: decreased appetite (29%), nausea (25%), and vomiting (23%).
  • Serious adverse reactions were reported in 29% of patients treated with GILOTRIF. The most frequent serious adverse reactions reported in patients treated with GILOTRIF were diarrhea (6.6%); vomiting (4.8%); and dyspnea, fatigue, and hypokalemia (1.7% each). Fatal adverse reactions in GILOTRIF-treated patients included pulmonary toxicity/ILD-like adverse reactions (1.3%), sepsis (0.43%), and pneumonia (0.43%).
  • More GILOTRIF-treated patients (2.2%) experienced ventricular dysfunction (defined as diastolic dysfunction, left ventricular dysfunction, or ventricular dilation; all < Grade 3) compared to chemotherapy-treated patients (0.9%).
Previously Treated, Metastatic Squamous NSCLC
  • In GILOTRIF-treated patients (n=392) the most common adverse reactions (≥20% all grades & vs erlotinib-treated patients (n=395)) were diarrhea (75% vs 41%), rash/acneiform dermatitis (70% vs 70%), stomatitis (30% vs 11%), decreased appetite (25% vs 26%), and nausea (21% vs 16%).
  • Serious adverse reactions were reported in 44% of patients treated with GILOTRIF. The most frequent serious adverse reactions reported in patients treated with GILOTRIF were pneumonia (6.6%), diarrhea (4.6%), and dehydration and dyspnea (3.1% each). Fatal adverse reactions in GILOTRIF-treated patients included ILD (0.5%), pneumonia (0.3%), respiratory failure (0.3%), acute renal failure (0.3%), and general physical health deterioration (0.3%).
DRUG INTERACTIONS
Effect of P-glycoprotein (P-gp) Inhibitors and Inducers
  • Concomitant use of P-gp inhibitors (including but not limited to ritonavir, cyclosporine A, ketoconazole, itraconazole, erythromycin, verapamil, quinidine, tacrolimus, nelfinavir, saquinavir, and amiodarone) with GILOTRIF can increase exposure to afatinib.
  • Concomitant use of P-gp inducers (including but not limited to rifampicin, carbamazepine, phenytoin, phenobarbital, and St. John's wort) with GILOTRIF can decrease exposure to afatinib.
USE IN SPECIFIC POPULATIONS
Lactation
  • Because of the potential for serious adverse reactions in breastfed infants from GILOTRIF, advise women not to breastfeed during treatment with GILOTRIF and for 2 weeks after the final dose.
Females and Males of Reproductive Potential
  • GILOTRIF may reduce fertility in females and males of reproductive potential. It is not known if the effects on fertility are reversible.
Renal Impairment
  • Patients with severe renal impairment (estimated glomerular filtration rate [eGFR] 15 to 29 mL/min/1.73 m2) 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. GILOTRIF has not been studied in patients with eGFR <15 mL/min/1.73 m2 or who are on dialysis.
Hepatic Impairment
  • GILOTRIF has not been studied in patients with severe (Child Pugh C) hepatic impairment. Closely monitor patients with severe hepatic impairment and adjust GILOTRIF dose if not tolerated.

GF PROF ISI 10.21.19

Please see full Prescribing Information, including Patient Information.

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  6. Data on file. Boehringer Ingelheim.
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NCCN=National Comprehensive Cancer Network® (NCCN®).