GIOTRIF

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-[[(3 S )-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-,(2 E )-, (2 Z )-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 C 32 H 33 ClFN 5 O 11, 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 and Coating: hypromellose, polyethylene glycol, titanium dioxide, talc, polysorbate 80, FD&C Blue No. 2 (40 mg and 30 mg tablets only).

is a kinase inhibitor indicated for: First-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have non-resistant epidermal growth factor receptor (EGFR) mutations as detected by an FDA-approved test Limitations of Use: Safety and efficacy of GILOTRIF were not established in patients whose tumors have resistant EGFR mutations Treatment of patients with metastatic, squamous NSCLC progressing after platinum-based chemotherapy 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 non-resistant epidermal growth factor receptor (EGFR) mutations as detected by an FDA-approved test.

The safety and efficacy of GILOTRIF have not been established in patients whose tumors have resistant EGFR mutations. 1.2 Previously Treated, Metastatic Squamous NSCLC GILOTRIF is indicated for the treatment of patients with metastatic squamous NSCLC progressing after platinum-based chemotherapy.

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.

Certain mutations in

EGFR, including non-resistant mutations in its kinase domain, can result in increased autophosphorylation of the receptor, leading to receptor activation, sometimes in the absence of ligand binding, and can support cell proliferation in NSCLC.

Non-resistant mutations are defined as those occurring in exons constituting the kinase domain of EGFR that lead to increased receptor activation and where efficacy is predicted by 1) clinically meaningful tumor shrinkage with the recommended dose of afatinib and/or 2) inhibition of cellular proliferation or EGFR tyrosine kinase phosphorylation at concentrations of afatinib sustainable at the recommended dosage according to validated methods.

The most commonly found of these mutations are exon 21 L858R substitutions and exon 19 deletions.

Afatinib demonstrated inhibition of autophosphorylation and/or in vitro proliferation of cell lines expressing wild-type EGFR and in those expressing selected EGFR exon 19 deletion mutations, exon 21 L858R mutations, or other less common non-resistant mutations, at afatinib concentrations achieved 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. 12.2 Pharmacodynamics Cardiac Electrophysiology The effect of multiple doses of GILOTRIF (50 mg once daily) on the QTc interval was evaluated in an open-label, single-arm study in patients with relapsed or refractory solid tumors.

No large changes in the mean

QTc interval (i.e., >20 ms) were detected in the study. 12.3 Pharmacokinetics Absorption Following oral administration of GILOTRIF tablets, time to peak afatinib plasma concentrations (T max ) is to 5 hours.

Maximum concentration (C max ) and area under the concentration-time curve from time zero to infinity (AUC 0-INF ) values increased slightly more than dose proportional in the range of to 50 mg. The geometric mean relative bioavailability of 20 mg GILOTRIF tablets was 92% as compared to an oral solution.

Steady-state plasma concentrations are achieved within 8 days of repeat dosing of GILOTRIF resulting in an accumulation of 2.8-fold for AUC and 2.1-fold for C max.

Effect of Food A high-fat meal decreased C max by 50% and AUC 0-INF by 39% relative to the fasted condition.

In vitro binding of afatinib to human plasma proteins is approximately 95%.

The elimination half-life of afatinib is 37 hours after repeat dosing in cancer patients.

Covalent adducts to proteins are the major circulating metabolites of afatinib and enzymatic metabolism of afatinib is minimal.

The metabolites formed by

CYP450-dependent reactions were approximately 9% of the total metabolic turnover in sandwich-cultured human hepatocytes.

Approximately 2% of the afatinib dose was metabolized by FMO3; the CYP3A4-dependent N-demethylation was not detected.

In humans, excretion of afatinib is primarily via the feces (85%) with 4% recovered in the urine following a single oral dose of [ 14 C]-labeled afatinib solution.

The parent compound accounted for 88% of the recovered dose.

Based on the population pharmacokinetic analysis, weight, gender, age, and race do not have a clinically important effect on exposure of afatinib.

A pharmacokinetic study was conducted in 14 subjects with normal (eGFR ≥90 mL/min/1.73 m 2 ) renal function, 8 subjects with moderate (eGFR to 59 mL/min/1.73 m 2 ) and 8 subjects with severe (eGFR to 29 mL/min/1.73 m 2 ) renal impairment.

All subjects received a single 40 mg oral dose of GILOTRIF.

The geometric mean AUC

INF for afatinib was 50% higher in subjects with severe renal impairment and was 22% higher in subjects with moderate renal impairment as compared to subjects with normal renal function.

Geometric mean

C max was 22% higher in subjects with severe renal impairment and was comparable in subjects with moderate renal impairment to subjects with normal renal function.

GILOTRIF has not been studied in patients with eGFR <15 mL/min/1.73 m 2 or on dialysis.

Mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment had no influence on the afatinib exposure following a single dose of GILOTRIF.

Subjects with severe (Child Pugh C) hepatic impairment have not been studied.

Drug Interactions Studies Clincial Studies Effect of P-gp Inhibitors and Inducers on Afatinib: The effect of ritonavir dosing time relative to a single oral dose of GILOTRIF was evaluated in healthy subjects taking 40 mg of GILOTRIF alone as compared to those after ritonavir (200 mg twice daily for 3 days) co-administration at 6 hours after GILOTRIF administration.

The relative bioavailability for

AUC 0-INF and C max of afatinib was 119% and 104% when co-administered with ritonavir, and 111% and 105% when ritonavir was administered 6 hours after taking GILOTRIF.

In another study, when ritonavir (200 mg twice daily for 3 days) was administered 1 hour before a 20 mg single dose of GILOTRIF, exposure to afatinib increased by 48% for AUC 0-INF and 39% for C max.

Pre-treatment with a potent inducer of

P-gp, rifampicin (600 mg once daily for 7 days) decreased the plasma exposure to afatinib by 34% (AUC 0-INF ) and 22% (C max ) .

In Vitro Studies Effect of Afatinib on P-gp: Based on in vitro data, afatinib is an inhibitor of P-gp.

Based on in vitro data, afatinib is a substrate and an inhibitor of the transporter BCRP.

Effect of Afatinib on

CYP450 Enzymes: Afatinib is not an inhibitor or an inducer of CYP450 enzymes (CYP1A2, 2B6, 2C8, 2C9, 2C19, and 3A4) in cultured primary human hepatocytes.

The following clinically significant adverse reactions are described elsewhere in the labeling: Diarrhea Bullous and Exfoliative Skin.

Disorders Interstitial Lung Disease Hepatic Toxicity Gastrointestinal Perforation Keratitis Most common adverse reactions (≥20%) were diarrhea, rash/acneiform dermatitis, stomatitis, paronychia, dry skin, decreased appetite, nausea, vomiting, pruritus.

To report SUSPECTED ADVERSE

REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data in the Warnings and Precautions section reflect exposure to GILOTRIF for clinically significant adverse reactions in 4257 patients enrolled in LUX-Lung 3 (n=229) and LUX-Lung 8 (n=392), and 3636 patients with cancer enrolled in 42 studies of GILOTRIF administered alone or in combination with other anti-neoplastic drugs at GILOTRIF doses ranging from 10-70 mg daily or at doses 10-160 mg in other regimens.

The mean exposure was 5.5 months.

The population included patients with various cancers, the most common of which were NSCLC, breast, colorectal, brain, and head and neck.

The data described below reflect exposure to GILOTRIF as a single agent in LUX-Lung 3, a randomized, active-controlled trial conducted in patients with EGFR mutation-positive, metastatic NSCLC, and in LUX-Lung 8, a randomized, active-controlled trial in patients with metastatic squamous NSCLC progressing after platinum-based chemotherapy.

EGFR Mutation-Positive Metastatic NSCLC The safety of GILOTRIF was evaluated in 229 EGFR-tyrosine kinase inhibitor-naïve patients with EGFR mutation-positive, metastatic non-squamous NSCLC enrolled in a randomized (2:1), multicenter, open-label trial (LUX-Lung 3).

Patients received either

GILOTRIF 40 mg daily until documented disease progression or intolerance to the therapy or pemetrexed 500 mg/m² followed after 30 minutes by cisplatin 75 mg/m² every three weeks for a maximum of six treatment courses.

The median exposure was 11 months for patients treated with GILOTRIF and 3.4 months for patients treated with pemetrexed/cisplatin.

The overall trial population had a median age of 61 years; 61% of patients in the GILOTRIF arm and 60% of patients in the pemetrexed/cisplatin arm were younger than 65 years.

A total of 64% of patients on GILOTRIF and 67% of pemetrexed/cisplatin patients were female.

More than two-thirds of patients were from Asia (GILOTRIF 70%; pemetrexed/cisplatin 72%).

Serious adverse reactions were reported in 29% of patients treated with GILOTRIF.

The most frequent serious adverse reactions reported in patients treated with GILOTRIF were diarrhea (6.6%); vomiting (4.8%); and dyspnea, fatigue, and hypokalemia (1.7% each).

Fatal adverse reactions in GILOTRIF-treated patients in LUX-Lung 3 included pulmonary toxicity/ILD-like adverse reactions (1.3%), sepsis (0.43%), and pneumonia (0.43%).

Dose reductions due to adverse reactions were required in 57% of GILOTRIF-treated patients.

The most frequent adverse reactions that led to dose reduction in the patients treated with GILOTRIF were diarrhea (20%), rash/acne (19%), paronychia (14%), and stomatitis (10%).

Discontinuation of therapy in

GILOTRIF-treated patients for adverse reactions was 14.0%.

The most frequent adverse reactions that led to discontinuation in GILOTRIF-treated patients were diarrhea (1.3%), ILD (0.9%), and paronychia (0.9%).

Clinical trials of

GILOTRIF excluded patients with an abnormal left ventricular ejection fraction (LVEF), i.e., below the institutional lower limit of normal.

In LUX-Lung 3, all patients were evaluated for LVEF at screening and every 9 weeks thereafter in the GILOTRIF-treated group and as needed in the pemetrexed/cisplatin group.

GILOTRIF-treated patients (2.2%; n=5) experienced ventricular dysfunction (defined as diastolic dysfunction, left ventricular dysfunction, or ventricular dilation; all.

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.

Recommended dosage: 40 mg orally once daily Renal impairment: 30 mg orally once daily in patients with severe renal impairment Instruct patients to take GILOTRIF at least 1 hour before or 2 hours after a meal 2.1 Patient Selection for Non-Resistant EGFR Mutation-Positive Metastatic NSCLC Select patients for first-line treatment of metastatic NSCLC with GILOTRIF based on the presence of non-resistant EGFR mutations in tumor specimens.

Information on FDA-approved tests for the detection of EGFR mutations in NSCLC is available at: . 2.2 Recommended Dosage The recommended dosage of GILOTRIF is 40 mg orally once daily until disease progression or no longer tolerated by the patient.

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 Dosage Modifications for Adverse Reactions Withhold GILOTRIF for: Grade 3 or higher adverse reactions Diarrhea of Grade 2 persisting for 2 or more consecutive days while taking anti-diarrheal medication Cutaneous reactions of Grade 2 that are prolonged (lasting more than 7 days) or intolerable 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.

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

Life-threatening bullous, blistering, or exfoliating skin lesions Confirmed interstitial lung disease (ILD) Severe drug-induced hepatic impairment Gastrointestinal perforation Persistent ulcerative keratitis Symptomatic left ventricular dysfunction Severe or intolerable adverse reaction occurring at a dose of 20 mg per day 2.4 Dosage Modification for Pre-Existing Severe Renal Impairment The recommended dosage of GILOTRIF in patients with pre-existing severe renal impairment (estimated glomerular filtration rate [eGFR] 15 to 29 mL/min /1.73 m 2 ) is 30 mg orally once daily. Use the Modification of Diet in Renal Disease [MDRD] formula to estimate eGFR. 2.5 Dosage Modifications for Drug Interactions P-glycoprotein 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.

GILOTRIF daily dose by 10 mg as tolerated for patients who require chronic therapy with a P-gp inducer.

Resume the previous dose to 3 days after discontinuation of the P-gp inducer.

tablets are available as follows: 40 mg: 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.

Unit of use bottles of 30 NDC: 0597-0138-30 30 mg: 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.

Unit of use bottles of 30 NDC: 0597-0137-30 20 mg: 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.

Unit of use bottles of 30 NDC: 0597-0141-30 Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) .

Dispense medication in the original container to protect from exposure to high humidity and light.

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) .

Dispense medication in the original container to protect from exposure to high humidity and light.

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.

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.

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).

Safety and effectiveness of

GILOTRIF in pediatric patients have not been established.

The safety and efficacy of afatinib were assessed, but not established, in a single-arm, open-label, multicenter trial [NCT02372006] which included 37 pediatric patients to <17 years of age with recurrent/refractory solid tumors with known ErbB pathway deregulation who received 80% of the adult dose per body surface area.

No new safety signals were observed in pediatric patients in this trial.

In these 37 patients, the pharmacokinetic parameters were within range of values in adults.

LUX-Lung 3 did not include sufficient numbers of subjects aged and over to determine whether they respond differently from younger subjects.

In LUX-Lung 8, 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

LUX-Lung 8, the hazard ratio for overall survival (OS) 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.