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Gilotrif

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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; some of these cases were fatal. In Study 1, diarrhea occurred in 96% of patients treated with GILOTRIF (n=229), of which 15% was Grade 3 in severity and occurred within the first 6 weeks [see ADVERSE REACTIONS]. Renal impairment as a consequence of diarrhea occurred in 6.1% of patients treated with GILOTRIF, out of which 3 (1.3%) were Grade 3.

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 6 (0.15%) of the 3865 patients who received GILOTRIF across clinical trials [see ADVERSE REACTIONS]. 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%. Discontinue GILOTRIF in patients who develop life-threatening bullous, blistering, or exfoliating lesions [see DOSAGE AND ADMINISTRATION]. 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].

Interstitial Lung Disease (ILD)

ILD or ILD-like adverse reactions (e.g., lung infiltration, pneumonitis, acute respiratory distress syndrome, or alveolitis allergic) occurred in 1.5% of the 3865 patients who received GILOTRIF across clinical trials; of these, 0.4% were fatal. The incidence of ILD appeared to be higher in patients of Asian ethnicity (2.1%) as compared to non-Asians (1.2%). In Study 1, the incidence of Grade ≥ 3 ILD was 1.3% and resulted in death in 1% 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 3865 patients who received GILOTRIF across clinical trials, 10.1% had liver test abnormalities, of which 7 (0.18%) were fatal. In Study 1, liver test abnormalities of any grade occurred in 17.5% of the patients treated with GILOTRIF.

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 0.8% of patients treated with GILOTRIF among 3865 patients across clinical trials. Keratitis was reported in 5 (2.2%) patients in Study 1, with Grade 3 in 1 (0.4%). 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.

Embryofetal Toxicity

Based on its mechanism of action, GILOTRIF can cause fetal harm when administered to a pregnant woman. Afatinib was embryotoxic and, in animals with maternal toxicity, led to abortions at late gestational stages in rabbits at doses of 5 mg/kg (approximately 0.2 times the human exposure at the recommended dose of 40 mg daily) or greater. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations].

Advise females of reproductive potential to use highly effective contraception during treatment, and for at least 2 weeks after the last dose of GILOTRIF. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking GILOTRIF [see Use in Specific Populations].

Patient Counseling Information

See 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, bleed or bruise 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.
  • Embryofetal Toxicity
    Counsel patients on pregnancy planning and prevention. Advise females of reproductive potential to use highly effective contraception during treatment, and for at least 2 weeks after taking the last dose of GILOTRIF [see WARNINGS AND PRECAUTIONS and Use In Specific Populations].
  • Nursing Mothers
    Advise patients to discontinue nursing while taking 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 MutaMouse.

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

Pregnancy Category D

Risk Summary

Based on its mechanism of action, GILOTRIF can cause fetal harm when administered to a pregnant woman. Afatinib was embryotoxic and, in animals with maternal toxicity, led to abortions at late gestational stages in rabbits 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. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see WARNINGS AND PRECAUTIONS].

Animal Data

Administration of afatinib to pregnant rabbits 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 embryofetal 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 at the recommended human dose of 40 mg daily).

Nursing Mothers

It is not known whether afatinib is present in human milk. Afatinib was present in the milk of lactating rats at concentrations 80-150 times higher than those found in plasma from 1 to 6 hours after administration. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from GILOTRIF, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

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

Geriatric Use

Of the 3865 patients in the clinical studies of GILOTRIF, 32% of patients were 65 years and older, while 7% were 75 years and older. No overall differences in safety were observed between patients 65 years and over and younger patients. In Study 1, 39% of the 345 patients were 65 years of age or older and 4% were 75 years or older. No overall differences in effectiveness were observed between patients 65 years and older and younger patients.

Females and Males of Reproductive Potential

Contraception

Females

Counsel patients on pregnancy planning and prevention. Advise female patients of reproductive potential to use highly effective contraception during treatment with GILOTRIF, and for at least 2 weeks after the last dose of GILOTRIF. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking GILOTRIF [see Use In Specific Populations].

Renal Impairment

GILOTRIF has not been studied in patients with severely impaired renal function (creatinine clearance [CLcr] < 30 mL/min). Adjustments to the starting dose of GILOTRIF are not considered necessary in patients with mild (CLcr 60-89 mL/min) renal impairment. Closely monitor patients with moderate (CLcr 30-59 mL/min) to severe (CLcr < 30 mL/min) renal impairment and adjust GILOTRIF dose if not tolerated [see 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 considered 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 CLINICAL PHARMACOLOGY].

Last reviewed on RxList: 12/4/2013
This monograph has been modified to include the generic and brand name in many instances.

Warnings
Precautions
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