July 24, 2016
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Gilotrif

"The U.S. Food and Drug Administration today approved Gilotrif (afatinib) for patients with late stage (metastatic) non-small cell lung cancer (NSCLC) whose tumors express specific types of epidermal growth factor receptor (EGFR) gene mutations, a"...

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Gilotrif

Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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 Study 1, 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 Study 2, 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].

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]. Provide patients with an anti-diarrheal agent (e.g., loperamide) for self-administration at the onset of diarrhea and instruct patients to continue anti-diarrheal therapy until loose bowel movements cease for 12 hours.

Bullous And Exfoliative Skin Disorders

Grade 3 cutaneous reactions characterized by bullous, blistering, and exfoliating lesions, occurred in 0.2% of the 4257 patients who received GILOTRIF across clinical trials. In Study 1, 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 Study 2, 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].

Discontinue GILOTRIF in patients who develop life-threatening bullous, blistering, or exfoliating lesions. For patients who develop prolonged Grade 2 cutaneous adverse reactions lasting more than 7 days, intolerable Grade 2, 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].

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].

Interstitial Lung Disease (ILD)

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 Study 1, the incidence of Grade ≥ 3 ILD was 1.3% and resulted in death in 1% of GILOTRIF-treated patients. In Study 2, 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].

Hepatic Toxicity

In 4257 patients who received GILOTRIF across clinical trials, 9.7% had liver test abnormalities, of which 0.2% were fatal. In Study 1, 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 Study 2, 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]. In patients who develop severe hepatic impairment while taking GILOTRIF, treatment should be discontinued.

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 Study 1, with Grade 3 in 0.4%. In Study 2, 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, treatment with GILOTRIF should be interrupted or discontinued [see DOSAGE AND ADMINISTRATION]. 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]. Contact lens use is also a risk factor for keratitis and ulceration.

Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, GILOTRIF can cause fetal harm when administered to a pregnant woman. Administration of afatinib to pregnant rabbits during organogenesis at exposures approximately 0.2 times the exposure in humans at the recommended dose of 40 mg daily resulted in embryotoxicity and, in rabbits showing maternal toxicity, increased abortions at late gestational stages. Advise pregnant women and females of reproductive potential of the potential risk to a fetus.

Advise females of reproductive potential to use effective contraception during treatment, and for at least 2 weeks after the last dose of GILOTRIF [see Use in Specific Populations].

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).

Diarrhea

Advise patients that diarrhea occurs in nearly all patients who receive GILOTRIF. Inform patients that diarrhea may result in dehydration and renal impairment if not treated. Advise patients to notify their physician if diarrhea develops and to seek medical attention promptly for severe or persistent diarrhea [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS].

Bullous And Exfoliative Skin Disorders

Advise patients to minimize sun exposure with protective clothing and use of sunscreen while taking GILOTRIF [see WARNINGS AND PRECAUTIONS].

Interstitial Lung Disease

Advise patients to immediately report any new or worsening lung symptoms, or any combination of the following symptoms: trouble breathing or shortness of breath, cough, fever [see WARNINGS AND PRECAUTIONS].

Hepatic Toxicity

Advise patients that they will need to undergo liver function monitoring periodically. Advise patients to immediately report any symptoms of a liver problem [e.g., skin or the whites of eyes turn yellow, urine turns dark or brown (tea colored), pain on the right side of stomach, bleeds or bruises more easily than normal, lethargy] [see WARNINGS AND PRECAUTIONS].

Keratitis

Advise patients to immediately report eye problems (e.g., eye pain, swelling, redness, blurred vision, or other vision changes) [see WARNINGS AND PRECAUTIONS].

Left Ventricular Dysfunction

Advise patients to contact a healthcare professional immediately for any of the following: new onset or worsening shortness of breath or exercise intolerance, cough, fatigue, swelling of the ankles/legs, palpitations, or sudden weight gain [see DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS].

Instructions For Taking GILOTRIF

Advise patients to take GILOTRIF on an empty stomach at least 1 hour before or 2 hours after eating [see DOSAGE AND ADMINISTRATION]. Advise patients not to take a missed dose within 12 hours of the next dose.

Embryo-Fetal Toxicity

Advise pregnant women and females of reproductive potential that GILOTRIF can result in fetal harm. Advise female patients to contact their healthcare provider with a known or suspected pregnancy. Advise females of reproductive potential to use effective contraception during treatment with GILOTRIF and for at least 2 weeks after the last dose of GILOTRIF [see Use In Specific Populations].

Lactation

Advise women not to breastfeed during treatment with GILOTRIF and for 2 weeks after the last dose of GILOTRIF [see Use in Specific Populations].

Infertility

Advise females and males of reproductive potential of the potential for reduced fertility from GILOTRIF [see Use in Specific Populations].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

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.

Use In Specific Populations

Pregnancy

Risk Summary

Based on findings from animal studies and its mechanism of action, GILOTRIF can cause fetal harm when administered to a pregnant woman. There are no available data on the use of GILOTRIF in pregnant women. 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 [see Data]. Advise a pregnant woman of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Animal Data

In an embryo-fetal development study in rabbits, administration of afatinib to pregnant animals at doses of 5 mg/kg (approximately 0.2 times the exposure by AUC at the recommended human dose of 40 mg daily) or greater during the period of organogenesis caused increased post-implantation loss, and in animals showing maternal toxicity, abortion at late gestational stages. In the same study, at the high dose level of 10 mg/kg (approximately 0.7 times the exposure by AUC at the recommended human dose of 40 mg daily), there were reduced fetal weights, and increases in the incidence of runts, as well as visceral and dermal variations. In an embryo-fetal development study in rats, there were skeletal alterations consisting of incomplete or delayed ossifications and reduced fetal weight at a dose of 16 mg/kg (approximately twice the exposure based on AUC at the recommended human dose of 40 mg daily).

Lactation

Risk Summary

There are no data on the presence of afatinib in human milk or its effects on the breastfed infant or on milk production. Afatinib was present in the milk of lactating rats [see Data]. Because of the potential for serious adverse reactions in nursing infants from GILOTRIF, advise a lactating woman not to breastfeed during treatment with GILOTRIF and for 2 weeks after the final dose.

Data

Afatinib was present in the milk of lactating rats at concentrations 80 and 150 times higher than those found in plasma at 1 and 6 hours after administration.

Females And Males Of Reproductive Potential

Contraception

Females

GILOTRIF can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with GILOTRIF, and for at least 2 weeks after the last dose of GILOTRIF [see Use in Specific Populations and CLINICAL PHARMACOLOGY].

Infertility

Based on results from an animal fertility study, GILOTRIF may reduce fertility in females and males of reproductive potential. It is not known if the effects on fertility are reversible [see Nonclinical Toxicology].

Pediatric Use

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

Geriatric Use

Study 1 did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

In Study 2, 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 Study 2, the hazard ratio for overall survival in patients less than 65 years old was 0.68 (95% CI: 0.55, 0.85) and in patients 65 years or older was 0.95 (95% CI: 0.76, 1.19). No overall differences in safety were observed between patients 65 years and older and younger patients.

Renal Impairment

Patients with severe renal impairment have a higher exposure to afatinib than patients with normal renal function. Administer GILOTRIF at a starting dose of 30 mg once daily in patients with severe renal impairment. Adjustments to the starting dose of GILOTRIF are not necessary in patients with mild or moderate renal impairment. Dosing recommendations for patients with eGFR < 15 mL/min/1.73 m² or on dialysis cannot be provided as GILOTRIF has not been studied in these patient populations [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].

Hepatic Impairment

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

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 5/9/2016

Warnings
Precautions

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