文案整理：Dr. Jasmine Ding
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
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 (1) 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 (2.2) ? 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
CONTRAINDICATIONS： None
WARNINGS AND PRECAUTIONS
Diarrhea:
Diarrhea may result in dehydration and renal failure. Withhold GILOTRIF for severe and prolonged diarrhea not responsive to antidiarrheal agents. (2.3, 5.1)
Bullous and Exfoliative Skin Disorders: Severe bullous, blistering, and exfoliating lesions occurred in 0.15% of patients. Discontinue for lifethreatening cutaneous reactions. Withhold GILOTRIF for severe and prolonged cutaneous reactions. (2.3, 5.2)
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. (2.3, 5.3)
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. (2.3, 5.4)
Keratitis: Occurs in 0.8% of patients. Withhold GILOTRIF for keratitis evaluation. Withhold or discontinue GILOTRIF for confirmed ulcerative keratitis. (2.3, 5.5)
Embryofetal toxicity: Can cause fetal harm. Advise females of the potential hazard to the fetus and to use highly effective contraception. (5.6)
ADVERSE REACTIONS
Most common adverse reactions (≥20%) are diarrhea, rash/dermatitis acneiform, stomatitis, paronychia, dry skin, decreased appetite, 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 Pgp inducers orally can decrease afatinib exposure. Increase GILOTRIF by 10 mg per day as tolerated.
USE IN SPECIFIC POPULATIONS
Nursing mothers: Discontinue drug or nursing (8.3) See 17 for PATIENT COUNSELING INFORMATION and FDAapproved patient labeling. Revised: 07/2013
FULL PRESCRIBING INFORMATION:
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Patient Selection
2.2 Recommended Dose
2.3 Dose Modification
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS
5.1 Diarrhea
5.2 Bullous and Exfoliative Skin Disorders
5.3 Interstitial Lung Disease (ILD)
5.4 Hepatic Toxicity
5.5 Keratitis
5.6 Embryofetal Toxicity
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
7 DRUG INTERACTIONS
8USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Females and Males of Reproductive Potential
8.7 Renal Impairment
8.8 Hepatic Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 3345502
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
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)]. Limitation of Use: Safety and efficacy of GILOTRIF have not been established in patients whose tumors have other EGFR mutations [see Clinical Studies (14)].
2 DOSAGE AND ADMINISTRATION
2.1 Patient Selection Select patients for the 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) and Clinical Studies (14)]. 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. 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 Modification
Withhold GILOTRIF for any drug-related adverse reactions of:
NCI CTCAE* Grade 3 or higher
Diarrhea of Grade 2 or higher persisting for 2 or more consecutive days while taking anti-diarrheal medication [see Warnings and Precautions
(5.1)] Cutaneous reactions of Grade 2 that are prolonged (lasting more than 7 days) or intolerable [see Warnings and Precautions (5.2)]
Renal dysfunction of Grade 2 or higher *National Cancer Institute Common Terminology Criteria for Adverse Events, 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: Life-threatening bullous, blistering, or exfoliative skin lesions [see Warnings and Precautions (5.2)]
Confirmed interstitial lung disease (ILD) [see Warnings and Precautions (5.3)]
Severe drug-induced hepatic impairment [see Warnings and Precautions (5.4)]
Persistent ulcerative keratitis [see Warnings and Precautions (5.5)]
Symptomatic left ventricular dysfunction
Severe or intolerable adverse reaction occurring at a dose of 20 mg per day P-gp Inhibitors For patients who require therapy with a P-glycoprotein (P-gp) inhibitor, reduce GILOTRIF daily dose by 10 mg if not tolerated. Resume the previous dose after discontinuation of the P-gp inhibitor as tolerated [see Drug Interactions (7) and Clinical Pharmacology (12.3)]. Reference ID: 3345502
P-gp Inducers For patients who require chronic therapy with a P-gp inducer, increase GILOTRIF daily dose by 10 mg as tolerated. 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 None
5 WARNINGS AND PRECAUTIONS
5.1 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 (6.1)]. 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 (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 6 (0.15%) of the 3865 patients who received GILOTRIF across clinical trials [see Adverse Reactions (6.1)]. 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 (2.3)]. 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)].
5.3 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 Reference ID: 3345502 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 (2.3)].
5.4 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 (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 0.8% 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 (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.
5.6 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 (8.1)]. 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 (8.1 and 8.6)].
6 ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the labeling:
Diarrhea [see Warnings and Precautions (5.1)]
Bullous and Exfoliative Skin Disorders [see Warnings and Precautions (5.2)]
Interstitial Lung Disease [see Warnings and Precautions (5.3)]
Hepatic Toxicity [see Warnings and Precautions (5.4)]
Keratitis [see Warnings and Precautions (5.5)]
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. Reference ID: 3345502
The safety evaluation of GILOTRIF is based on the data from more than 3800 patients, including 2135 NSCLC patients receiving GILOTRIF monotherapy at or above the recommended dose. Controlled Study The data in Tables 1 and 2 below reflect exposure of 229 EGFR-TKI naive GILOTRIF-treated patients with EGFR mutation-positive, metastatic, non-squamous, NSCLC enrolled in a randomized, multicenter, open-label trial (Study 1). Patients received GILOTRIF 40 mg daily until documented disease progression or intolerance to the therapy. A total of 111 patients were treated with pemetrexed/cisplatin. Patients were treated with 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 11.0 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 Study 1 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 Study 1, 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. More GILOTRIF-treated patients (2.2%; n=5) experienced ventricular dysfunction (defined as diastolic dysfunction, left ventricular dysfunction, or ventricular dilation; all < Grade 3) compared to chemotherapy-treated patients (0.9%; n=1). Reference ID: 3345502 Table 1 Adverse Reactions Reported in ≥10% of GILOTRIF-Treated Patients in Study 1
GILOTRIF n=229 Pemetrexed/Cisplatin n=111 Adverse Reaction All Grades (%) Grade 3* (%) All Grades (%) Grade 3* (%) Gastrointestinal disorders Diarrhea 96 15 23 2 Stomatitis1 71 9 15 1 Cheilitis 12 0 1 0 Skin and subcutaneous tissue disorders Rash/Dermatitis acneiform2 90 16 11 0 Pruritus 21 0 1 0 Dry skin 31 0 2 0 Infections and infestations Paronychia3 58 11 0 0 Cystitis 13 1 5 0 Metabolism and nutrition disorders Decreased appetite 29 4 55 4 Respiratory, thoracic and mediastinal disorders Epistaxis 17 0 2 1 Rhinorrhea 11 0 6 0 Investigations Weight decreased 17 1 14 1 General disorders and administration site conditions Pyrexia 12 0 6 0 Eye disorders Conjunctivitis 11 0 3 0 *None of the adverse reactions in this table were Grade 4 in severity 1 Includes stomatitis, aphthous stomatitis, mucosal inflammation, mouth ulceration, oral mucosa erosion, mucosal erosion, mucosal ulceration 2 Includes group of rash preferred terms, acne, acne pustular, dermatitis acneiform 3 Includes paronychia, nail infection, nail bed infection Table 2 Adverse Reactions of Laboratory Abnormalities from the Investigations SOC Reported in ≥5% of GILOTRIF-Treated Patients in Study 1 GILOTRIF n=229 Pemetrexed/Cisplatin n=111 Adverse Reaction All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Alanine aminotransferase increased 11 2 4 0 Hypokalemia1 11 4 5 4 Aspartate aminotransferase increased 8 2 2 1 1 Includes hypokalemia, blood potassium decreased SOC=system organ class
DRUG INTERACTIONS
Effect of P-glycoprotein (P-gp) Inhibitors and Inducers
Oral administration of a P-gp inhibitor (ritonavir at 200 mg twice daily) 1 hour before administration of GILOTRIF increased systemic exposure to afatinib by 48%. There was no change in afatinib exposure when ritonavir was administered simultaneously with or 6 hours after GILOTRIF. Concomitant taking of P-gp inhibitors (including but not limited to ritonavir, cyclosporine A, ketoconazole, itraconazole, erythromycin, verapamil, quinidine, tacrolimus, nelfinavir, saquinavir, and amiodarone) with GILOTRIF can increase exposure to afatinib [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)]. Reference ID: 3345502 7 8
Co-administration with oral dose of a P-gp inducer (rifampicin at 600 mg once daily for 7 days) decreased exposure to afatinib by 34%. Concomitant taking of P-gp inducers (including but not limited to rifampicin, carbamazepine, phenytoin, phenobarbital, and St. John’s wort) with GILOTRIF can decrease exposure to afatinib [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].
USE IN SPECIFIC POPULATIONS
8.1 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 (5.6)]. 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).
8.3 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.
8.4 Pediatric Use Safety and effectiveness of GILOTRIF in pediatric patients have not been established.
8.5 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.
8.6 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 Reference ID: 3345502 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)].
8.7 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)].
8.8 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). Reference ID: 3345502
12 CLINICAL PHARMACOLOGY
12.1 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 wildtype 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.
12.2 Pharmacodynamics
Cardiac Electrophysiology The effect of multiple doses of GILOTRIF (50 mg once daily) on the QTc interval was evaluated in an openlabel, 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 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-∞) values 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 fasted condition [see Dosage and Administration (2.2)].
Metabolism and Elimination
Covalent adducts to proteins are the major circulating metabolites of afatinib and enzymatic metabolism of afatinib is minimal. In humans, excretion of afatinib is primarily via the feces (85%) with 4% recovered in the urine following a single oral dose of [14C]-labeled afatinib solution. The parent compound accounted for 88% of the recovered dose. The elimination half-life of afatinib is 37 hours after repeat dosing in cancer patients. 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 Cmax. Specific Populations
Renal Impairment: The median trough afatinib plasma concentrations in patients with mild (CLcr 60-89 mL/min) and moderate (CLcr 30-59 mL/min) renal impairment were 27% and 85% higher than those in patients with normal renal function (CLcr ≥90 mL/min). GILOTRIF has not been studied in patients with severely impaired renal function (CLcr <30 mL/min) [see Use in Specific Populations (8.7)].
Hepatic Impairment: Afatinib is eliminated mainly by biliary/fecal excretion. Mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment had no influence on the afatinib exposure following a single dose of Reference ID: 3345502 GILOTRIF. Subjects with severe (Child Pugh C) hepatic dysfunction have not been studied [see Use in Specific Populations (8.8)]. Body Weight, Gender, Age, and Race: Based on the population pharmacokinetic analysis, weight, gender, age, and race do not have a clinically important effect on exposure of afatinib. Drug Interactions 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 AUC0-∞ and Cmax 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 AUC0-∞ and 39% for Cmax [see Drug Interactions (7)]. 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% (AUC0-∞) and 22% (Cmax) [see Drug Interactions (7)]. P-glycoprotein (P-gp): Based on in vitro data, afatinib is a substrate and an inhibitor of P-gp. Breast Cancer Resistance Protein (BCRP): Based on in vitro data, afatinib is a substrate and an inhibitor of the transporter BCRP. Effect of CYP450 Enzyme Inducers and Inhibitors on Afatinib: In vitro data indicated that drug-drug interactions with GILOTRIF due to inhibition or induction of CYP450 enzymes by concomitant medications are unlikely. The metabolites formed by CYP450-dependent reactions were approximately 9% of the total metabolic turnover in sandwich-cultured human hepatocytes. In humans, enzyme-catalyzed metabolic reactions play a negligible role for the metabolism of afatinib. Approximately 2% of the afatinib dose was metabolized by FMO3; the CYP3A4-dependent N-demethylation was not detected.
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. Therefore, afatinib is unlikely to affect the metabolism of other drugs that are substrates of CYP450 enzymes.
13 NONCLINICAL TOXICOLOGY
13.1 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 Muta? Mouse. 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 Reference ID: 3345502 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.
14 CLINICAL STUDIES
Non-small Cell Lung Cancer (NSCLC)
Study 1
The efficacy and safety of GILOTRIF in the first-line treatment of 345 patients with EGFR mutation-positive, metastatic (Stage IV and Stage IIIb with pleural and/or pericardial effusion as classified by the American Joint Commission on Cancer [AJCC, 6th edition]) NSCLC were established in a randomized, multicenter, open-label trial (Study 1). Patients were randomized (2:1) to receive GILOTRIF 40 mg orally once daily (n=230) or up to 6 cycles of pemetrexed/cisplatin (n=115). Randomization was stratified according to EGFR mutation status (exon 19 deletion vs exon 21 L858R vs other) and race (Asian vs non-Asian). The major efficacy outcome was progression-free survival (PFS) as assessed by an independent review committee (IRC). Other efficacy outcomes included objective response rate (ORR) and overall survival (OS). EGFR mutation status was prospectively determined for screening and enrollment of patients by a clinical trial assay (CTA). Tumor samples from 264 patients (178 randomized to GILOTRIF and 86 patients randomized to chemotherapy) were tested retrospectively by the companion diagnostic therascreen? EGFR RGQ PCR Kit, which is FDA-approved for selection of patients for GILOTRIF treatment. Among the patients randomized, 65% were female, the median age was 61 years, the baseline ECOG performance status was 0 (39%) or 1 (61%), 26% were Caucasian and 72% were Asian. The majority of the patients had a tumor sample with an EGFR mutation categorized by the CTA as either exon 19 deletion (49%) or exon 21 L858R substitution (40%), while the remaining 11% had other mutations. A statistically significant improvement in PFS as determined by the IRC was demonstrated for patients randomized to GILOTRIF compared with those randomized to chemotherapy. See Table 3 and Figure 1. There was no statistically significant difference for overall survival between the treatment arms at the interim analysis conducted at 84% of the planned events for the final analysis. Reference ID: 3345502 Table 3: Efficacy Results of Study 1 GILOTRIF (N=230) Pemetrexed/Cisplatin (N=115) Progression-free Survival Number of Deaths or Progressions, N (%) 152 (66.1%) 69 (60.0%) Median Progression-free Survival (months) 11.1 6.9 95% CI (9.6, 13.6) (5.4, 8.2) HR (95% CI) 0.58 (0.43, 0.78) Stratified Log-Rank Test P-value* <0.001 Overall Survival Number of Deaths, N (%) 116 (50.4%) 59 (51.2%) Median Overall Survival (months) 28.1 28.2 95% CI (24.6, 33.0) (20.7, 33.2) HR (95% CI) 0.91 (0.66, 1.25) Stratified Log-Rank Test P-value* 0.55 Objective Response Rate (CR + PR) N (%) 116 (50.4%) 22 (19.1%) Response Duration Median (months) 12.5 6.7 *Stratified by EGFR mutation status and race. CR=complete response; PR=partial response Figure 1 Kaplan-Meier Curve for PFS by Independent Review by Treatment Group Subgroup analyses were conducted based on the stratification factor of EGFR mutation status (Del19, L858R, other) and mutation category (common [Del19, L858R] vs uncommon [other]). See Figure 2. Reference ID: 3345502 Figure 2 Forest Plot of PFS and OS for Common (Del19, L858R) and Uncommon (other) EGFR Mutation Categories There were 26 GILOTRIF-treated patients in the “other” (uncommon) EGFR mutations subgroup with nine unique mutation patterns. None of these 26 patients achieved a complete response, while four achieved a partial response (see Table 4 below). No responses were seen in GILOTRIF-treated patients with the following mutations: T790M alone (n=2), deletion 19 and T790M (n=3), G719X and T790M (n=1), exon 20 insertion (n=6), and L861Q alone (n=3). There were 11 chemotherapy-treated patients in the “other” uncommon EGFR mutation subgroup; of these, four (36%) achieved a partial response. Table 4 Objective Tumor Responses in GILOTRIF-Treated Patients Based on Investigator Assessment in the “Other” (Uncommon) EGFR Mutation Subgroup EGFR Mutations Number of GILOTRIFTreated Patients Number of Patients with Partial Responses Duration of Response L858R and T790M 5 1 6.9 months L858R and S768I 2 1 12.4+ months S768I 1 1 16.5+ months G719X 3 1 9.6 months + Censored observation
16 HOW SUPPLIED/STORAGE AND HANDLING
GILOTRIF 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. Reference ID: 3345502 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 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]. Dispense medication in the original container to protect from exposure to high humidity and light.
17 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 (5.1) and Adverse Reactions (6.1)].
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 (5.2)].
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 (5.3)].
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 (5.4)].
Keratitis
Advise patients to immediately report eye problems (e.g., eye pain, swelling, redness, blurred vision, or other vision changes) [see Warnings and Precautions (5.5)].
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 (2.3) and Adverse Reactions (6.1)]. Reference ID: 3345502 ? 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 (2.2)]. 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 (5.6) and Use in Specific Populations (8.1)].
Nursing Mothers
Advise patients to discontinue nursing while taking GILOTRIF [see Use in Specific Populations (8.3)].
Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA
Licensed from: Boehringer Ingelheim International GmbH
GILOTRIF is a trademark of and used under license from Boehringer Ingelheim International GmbH.
The other brands listed are trademarks of their respective owners and are not trademarks of Boehringer Ingelheim Pharmaceuticals, Inc.
Copyright 2013 Boehringer Ingelheim International GmbH
ALL RIGHTS RESERVED
IT5562BG172013
302972-01
