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GILOTRIF (afatinib) tablets
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use GILOTRIF safely and effectively. See full prescribing information for GILOTRIF.
GILOTRIF ® (afatinib) tablets, for oral use
Initial U.S. Approval: 2013
RECENT MAJOR CHANGES
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Indications and Usage, |
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Previously Treated, Metastatic Squamous NSCLC (1.2) |
4/2016 |
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Dosage and Administration, Recommended Dose (2.2) |
4/2016 |
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Warnings and Precautions (5) |
4/2016 |
INDICATIONS AND USAGE
GILOTRIF is a kinase inhibitor indicated for:
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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 (1.1)
Limitation of Use: Safety and efficacy of GILOTRIF were not established in patients whose tumors have other EGFR mutations (1.1)
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Treatment of patients with metastatic, squamous NSCLC progressing after platinum-based chemotherapy (1.2)
DOSAGE AND ADMINISTRATION
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Recommended dose: 40 mg orally, once daily (2.2)
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Renal impairment: 30 mg orally, once daily in patients with severe renal impairment (2.2, 8.6, 12.3)
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Instruct patients to take GILOTRIF at least 1 hour before or 2 hours after a meal (2)
DOSAGE FORMS AND STRENGTHS
Tablets: 40 mg, 30 mg, and 20 mg (3)
CONTRAINDICATIONS
None. (4)
WARNINGS AND PRECAUTIONS
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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)
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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)
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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)
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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)
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Keratitis: Occurs in 0.7% of patients. Withhold GILOTRIF for keratitis eva luation. Withhold or discontinue GILOTRIF for confirmed ulcerative keratitis. (2.3, 5.5)
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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. (5.6)
ADVERSE REACTIONS
Most common adverse reactions (≥20%) were diarrhea, rash/acneiform dermatitis, stomatitis, paronychia, dry skin, decreased appetite, nausea, vomiting, pruritus (6.1).
To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at (800) 542-6257 or (800) 459-9906 TTY or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
DRUG INTERACTIONS
Co-administration of P-gp inhibitors can increase afatinib exposure. Reduce GILOTRIF by 10 mg per day if not tolerated. Co-administration of chronic P-gp inducers orally can decrease afatinib exposure. Increase GILOTRIF by 10 mg per day as tolerated. (2.3, 7)
USE IN SPECIFIC POPULATIONS
Lactation: Advise women not to breastfeed (8.2)
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 4/2016
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
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 epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test [see Clinical Studies (14.1)].
Limitation of Use: The safety and efficacy of GILOTRIF have not been established in patients whose tumors have other EGFR mutations [see Clinical Studies (14.1)].
1.2 Previously Treated, Metastatic Squamous NSCLC
GILOTRIF is indicated for the treatment of patients with metastatic squamous NSCLC progressing after platinum-based chemotherapy [see Clinical Studies (14.2)].
2 DOSAGE AND ADMINISTRATION
2.1 Patient Selection for EGFR Mutation-Positive Metastatic NSCLC
Select patients for first-line treatment of metastatic NSCLC with GILOTRIF based on the presence of EGFR exon 19 deletions or exon 21 (L858R) substitution mutations in tumor specimens [see Indications and Usage (1.1) and 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.
2.2 Recommended Dose
The recommended dose of GILOTRIF is 40 mg orally, once daily until disease progression or no longer tolerated by the patient.
Severe Renal Impairment
The recommended dose of GILOTRIF in patients with 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) and Clinical Pharmacology (12.3)].
*Use the Modification of Diet in Renal Disease [MDRD] formula to estimate eGFR.
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.
2.3 Dose Modifications for Adverse Reactions
Withhold GILOTRIF for any adverse reactions of:
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NCI CTCAE* Grade 3 or higher
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Diarrhea of Grade 2 or higher persisting for 2 or more consecutive days while taking anti-diarrheal medication [see Warnings and Precautions (5.1)]
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Cutaneous reactions of Grade 2 that are prolonged (lasting more than 7 days) or intolerable [see Warnings and Precautions (5.2)]
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Renal impairment of Grade 2 or higher [see Warnings and Precautions (5.1)]
*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:
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Life-threatening bullous, blistering, or exfoliative skin lesions [see Warnings and Precautions (5.2)]
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Confirmed interstitial lung disease (ILD) [see Warnings and Precautions (5.3)]
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Severe drug-induced hepatic impairment [see Warnings and Precautions (5.4)]
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Persistent ulcerative keratitis [see Warnings and Precautions (5.5)]
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Symptomatic left ventricular dysfunction [see Adverse Reactions (6.1)]
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Severe or intolerable adverse reaction occurring at a dose of 20 mg per day
2.4 Dose Modifications for Drug Interactions
P-gp Inhibitors
Reduce GILOTRIF daily dose by 10 mg if not tolerated for patients who require therapy with a P-glycoprotein (P-gp) inhibitor. Resume the previous dose after discontinuation of the P-gp inhibitor as tolerated [see Drug Interactions (7) and Clinical Pharmacology (12.3)].
P-gp Inducers
Increase GILOTRIF daily dose by 10 mg as tolerated for patients who require chronic therapy with a P-gp inducer. Resume the previous dose 2 to 3 days after discontinuation of the P-gp inducer [see Drug Interactions (7) and Clinical Pharmacology (12.3)].
3 DOSAGE FORMS AND STRENGTHS
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.
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
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 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 (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.
5.2 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 (6.1)].
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 (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)].
5.3 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 eva luation of patients with suspected ILD, and discontinue GILOTRIF in patients with confirmed ILD [see Dosage and Administration (2.3)].
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 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 (2.3)]. In patients who develop severe hepatic impairment while taking GILOTRIF, treatment should be discontinued.
5.5 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 eva luation 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 (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.
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