IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
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 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
- Withhold GILOTRIF during evaluation of patients with suspected ILD, and discontinue GILOTRIF in patients
with confirmed ILD.
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. Treatment should be discontinued in patients who develop severe
hepatic impairment while taking GILOTRIF.
Keratitis has been reported in patients taking GILOTRIF.
Withhold GILOTRIF during evaluation of patients with suspected keratitis. If diagnosis of ulcerative keratitis is
confirmed, treatment with GILOTRIF should be interrupted or discontinued. 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.
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 observed in clinical trials were as follows:
First‑line treatment of EGFR mutation‑positive, metastatic non‑small cell lung cancer (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%).
Pancreatitis has been reported during post‑marketing use of GILOTRIF. The frequency and causal relationship
of pancreatitis to GILOTRIF has not been established.
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
Because of the potential for serious adverse reactions in nursing infants from GILOTRIF, lactating women
should not 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.
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.
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.
INDICATIONS AND USAGE
GILOTRIF (afatinib) is indicated for the first‑line treatment of patients with metastatic non‑small cell lung
cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21
(L858R) substitution mutations as detected by an FDA‑approved test.
Limitation of Use: Safety and efficacy of GILOTRIF have not been established in patients whose tumors have other EGFR mutations.
- GILOTRIF is indicated for the treatment of patients with metastatic squamous NSCLC progressing after
GF PROF ISI July 2016
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