he 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 (8.1)].
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 (12.3)].
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 (12.3)].
10 OVERDOSAGE
Overdose was reported in 2 healthy adolescents each of whom ingested 360 mg of Gilotrif (as part of a mixed-drug ingestion) resulting in nausea, vomiting, asthenia, dizziness, headache, abdominal pain, and elevated amylase (<1.5 times upper limit of normal [ULN]). Both subjects recovered.
11 DESCRIPTION
Gilotrif tablets contain afatinib, a tyrosine kinase inhibitor which is a 4-anilinoquinazoline. Afatinib is presented as the dimaleate salt, with the chemical name 2-butenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-,(2E)-, (2Z)-2-butenedioate (1:2). Its structural formula is:
Afatinib dimaleate is a white to brownish yellow powder, water soluble and hygroscopic, with an empirical formula of C32H33ClFN5O11, and a molecular weight of 718.1 g/mol.
Gilotrif tablets for oral administration are available in 40 mg, 30 mg, or 20 mg of afatinib (equivalent to 59.12 mg, 44.34 mg, or 29.56 mg afatinib dimaleate, respectively). The inactive ingredients of Gilotrif are the following: Tablet Core: lactose monohydrate, microcrystalline cellulose, crospovidone, colloidal silicon dioxide, magnesium stearate. Coating: hypromellose, polyethylene glycol, titanium dioxide, talc, polysorbate 80, FD&C Blue No. 2 (40 mg and 30 mg tablets only).
12 CLINICAL PHARMACOLOGY
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.
Treatment with afatinib resulted in inhibition of tumor growth in nude mice implanted with tumors either overexpressing wild type EGFR or HER2 or in an EGFR L858R/T790M double mutant model.
Pharmacodynamics
Cardiac Electrophysiology
The effect of multiple doses of Gilotrif (50 mg once daily) on the QTc in |
