Afatinib- (Gilotrif tablets )-@- (July 2013)- Chemotherapeutic AgentsDrug Name:
Afatinib- (Gilotrif tablets )-@- (July 2013)- Chemotherapeutic Agents
List Of Brands:
Indication Type Description:
Dosages/ Overdosage Etc
Pregnancy and lactation
Co-administration of P-gp inhibitors can increase afatinib exposure.
Reduce GILOTRIF by 10 mg per day if not tolerated.
Co-administration of chronic Pgp inducers orally can decrease afatinib
exposure. Increase GILOTRIF by 10 mg per day as tolerated.
GILOTRIF. (afatinib) tablets, for oral use
Initial U.S. Approval: 2013
Drug Name- Gilotrif
Active Ingredient - Aftatinib
For patients with late stage (metastatic) non-small cell lung cancer (NSCLC)
whose tumors express specific type of epidermal growth factor receptor (EGFR)
gene mutations, as detected by an FDA approved test
Metastatic non-small lung cancer (NSCLC)
Approved by FDA on 12-7--2013 (Ref- FDA approved List- 2013)
Proprietary Name- GILOTRIF TABLETS*
Established Name- Gilotrif
Applicant- BOEHRINGER INGELHEIM PHARMACEUTICALS INC.
Indication- For the first-line treatment of patients with metstatic small lung
cancer NSCLC) whose tumors have epidermal growth factor EGFR
exon 19 deletions or exon 21 (L858R mutation, as approved by
Safety and efficacy of afatanib have not been established in
patients whose tumors have other EGFR mutations.
Concurrent with this action, FDA approved the therascreen
EGFR RGQ PCR kit.(QIAGEN) for detection of EGFR
exon 19 deletions or exon 21 (LGFR) substitution mutations.
Approval Date- July 12,2013
Approved by U.S.FDA (Ref- FDA approved List- 2013)
Most common adverse reactions (.20%) are diarrhea, rash/dermatitis
acneiform, stomatitis, paronychia, dry skin, decreased appetite, pruritus
WARNINGS AND PRECAUTIONS
Diarrhea: Diarrhea may result in dehydration and renal failure.
Withhold GILOTRIF for severe and prolonged diarrhea not
responsive to antidiarrheal agents.
Bullous and Exfoliative Skin Disorders: Severe bullous, blistering,
and exfoliating lesions occurred in 0.15% of patients.
Discontinue for life-threatening cutaneous reactions.
Withhold GILOTRIF for severe and prolonged cutaneous reactions.
Interstitial lung disease (ILD): Occurs in 1.5% of patients.
Withhold GILOTRIF for acute onset or worsening of pulmonary symptoms.
Discontinue GILOTRIF if ILD is diagnosed.
Hepatic toxicity: Fatal hepatic impairment occurs in 0.18% of patients.
Monitor with periodic liver testing.
Withhold or discontinue GILOTRIF for severe or worsening liver tests.
Keratitis: Occurs in 0.8% of patients. Withhold GILOTRIF for keratitis
Withhold or discontinue GILOTRIF for confirmed ulcerative keratitis.
Embryofetal toxicity: Can cause fetal harm. Advise females of the
potential hazard to the fetus and to use highly effective contraception.
Dosages/ Overdosage Etc:
INDICATIONS AND USAGE
GILOTRIF is a kinase inhibitor 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
DOSAGE AND ADMINISTRATION
Recommended dose: 40 mg orally, once daily
Instruct patients to take GILOTRIF at least 1 hour before
or 2 hours after a meal
DOSAGE FORMS AND STRENGTHS
Tablets:40 mg, 30 mg, and 20 mg
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
Bullous and Exfoliative Skin Disorders
Advise patients to minimize sun exposure with protective clothing and use of
sunscreen while taking GILOTRIF
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
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)
Advise patients to immediately report eye problems (e.g., eye pain, swelling, redness
blurred vision, or other vision changes)
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
Instructions for Taking GILOTRIF
Advise patients to take GILOTRIF on an empty stomach at least 1 hour before
or 2 hours after eating
Advise patients not to take a missed dose within 12 hours of the next dose.
„h Embryofetal Toxicity
Counsel patients on pregnancy planning and prevention. Advise females o
reproductive potential to use highly effective contraception during treatment,
and for at least 2 weeks after taking the last dose of GILOTRIF
Advise patients to discontinue nursing while taking GILOTRIF .
1. Mechanism of Action
Afatinib covalently binds to the kinase domains of EGFR (ErbB1), HER2 (ErbB2),
and HER4 (ErbB4) and irreversibly inhibits tyrosine kinase autophosphorylation,
resulting in downregulation of ErbB signaling.
Afatinib demonstrated inhibition of autophosphorylation and in vitro proliferation
of cell lines expressing wild-type EGFR or those expressing selected
EGFR exon 19 deletion mutations or exon 21 L858R mutations, including some
with a secondary T790M mutation, at afatinib concentrations achieved,
at least transiently, in patients. In addition, afatinib inhibited in vitro proliferation
of cell lines overexpressing HER2.
Absorption and Distribution
Following oral administration of GILOTRIF tablets, time to peak afatinib plasma
concentrations (Tmax) is 2 to 5 hours. Maximum concentration (Cmax) and area
under the concentration-time curve from time zero to infinity (AUC0-‡) value
increased slightly more than dose proportional in the range of 20 to 50 mg.
The geometric mean relative bioavailability of 20 mg GILOTRIF tablets was 92%
as compared to an oral solution. In vitro binding of afatinib to human plasma
proteins is approximately 95%.
A high-fat meal decreased Cmax by 50% and AUC0-‡ by 39% relative to the
Pregnancy and lactation:
USE IN SPECIFIC POPULATIONS
Pregnancy Category D
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
2. 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.
3. Pediatric Use
Saf.ety and effectiveness of GILOTRIF in pediatric patients have not been established.
4. 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.