Erlotinib tablet is a kinase inhibitor indicated for: The 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 receiving first-line, maintenance, or second or greater line treatment after progression following at least one prior chemotherapy regimen ( 1.1 ) First-line treatment of patients with locally advanced, unrespectable or metastatic pancreatic cancer, in combination with gemcitabine.
( 1.2 ) Limitations of Use: Safety and efficacy of erlotinib tablets have not been established in patients with NSCLC whose tumors have other EGFR mutations. ( 1.1 ) Erlotinib tablets are not recommended for use in combination with platinum-based chemotherapy. ( 1.1 )
1.1Non-Small Cell Lung Cancer (NSCLC) Erlotinib
Tablets was indicated for: The 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 receiving first-line, maintenance, or second or greater line treatment after progression following at least one prior chemotherapy regimen [see Clinical Studies (14.1 , 14.3) ] .
Limitations of use: Safety and efficacy of erlotinib have not been established in patients with NSCLC whose tumors have other EGFR mutations [see Clinical Studies (14.1, 14.2) ]. Erlotinib tablet is not recommended for use in combination with platinum-based chemotherapy [see Clinical Studies ( 14.4 )].
1.2Pancreatic Cancer
Erlotinib tablet in combination with gemcitabine is indicated for the first-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer [see Clinical Studies (14.5) ] .
Contraindications
None None ( 4 )
Warnings and precautions
Interstitial lung disease (ILD) : Occurs in 1.1% of patients. Withhold erlotinib tablets for acute onset of new or progressive unexplained pulmonary symptoms, such as dyspnea, cough and fever. Discontinue erlotinib if ILD is diagnosed. ( 5.1 ) Renal failure : Monitor renal function and electrolytes, particularly in patients at risk of dehydration. Withhold erlotinib tablets for severe renal toxicity. ( 5.2 ) Hepatotoxicity : Occurs with or without hepatic impairment, including hepatic failure and hepatorenal syndrome: Monitor periodic liver testing.
Withhold or discontinue erlotinib tablets for severe or worsening liver tests. ( 5.3 ) Gastrointestinal perforations : Discontinue erlotinib tablets. ( 5.4 ) Bullous and exfoliative skin disorders : Discontinue erlotinib tablets. ( 5.5 ) Cerebrovascular accident (CVA) : The risk of CVA is increased in patients with pancreatic cancer. ( 5.6 ) Microangiopathic hemolytic anemia (MAHA) : The risk of MAHA is increased in patients with pancreatic cancer.
( 5.7 ) Ocular disorders : Discontinue erlotinib tablets for corneal perforation, ulceration or persistent severe keratitis. ( 5.8 ) Hemorrhage in patients taking warfarin : Regularly monitor INR in patients taking warfarin or other coumarin-derivative anticoagulants. ( 5.9 ) Embryo-fetal toxicity : Can cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception.( 5.10 , 8.1 , 8.3 )
5.1Interstitial Lung Disease (ILD) Cases
of serious ILD, including fatal cases, can occur with erlotinib tablets treatment. The overall incidence of ILD in approximately 32,000 erlotinib tablets-treated patients in uncontrolled studies and studies with concurrent chemotherapy was approximately 1.1%. In patients with ILD, the onset of symptoms was between 5 days to more than 9 months (median 39 days) after initiating erlotinib tablets therapy. Withhold erlotinib tablets for acute onset of new or progressive unexplained pulmonary symptoms such as dyspnea, cough, and fever pending diagnostic evaluation.
If ILD is confirmed, permanently discontinue erlotinib tablets [see Dosage and Administration (2.4) ] .
5.2 Renal failure Hepatorenal syndrome, severe acute renal failure including fatal cases, and renal insufficiency can occur with erlotinib tablet treatment. Renal failure may arise from exacerbation of underlying baseline hepatic impairment or severe dehydration. The pooled incidence of severe renal impairment in the 3 monotherapy lung cancer studies was 0.5% in the erlotinib tablets arms and 0.8% in the control arms. The incidence of renal impairment in the pancreatic cancer study was 1.4% in the erlotinib tablet plus gemcitabine arm and 0.4% in the control arm.
Withhold erlotinib tablet in patients developing severe renal impairment until renal toxicity is resolved. Perform periodic monitoring of renal function and serum electrolytes during erlotinib tablet treatment [see Adverse Reactions (6.1) and Dosage and Administration (2.4) ] .
5.3Hepatotoxicity with or without Hepatic Impairment
Hepatic failure and hepatorenal syndrome, including fatal cases, can occur with erlotinib tablet treatment in patients with normal hepatic function; the risk of hepatic toxicity is increased in patients with baseline hepatic impairment. In clinical studies where patients with moderate to severe hepatic impairment were excluded, the pooled incidence of hepatic failure in the 3 monotherapy lung cancer studies was 0.4% in the erlotinib tablet arms and 0% in the control arms.
The incidence of hepatic failure in the pancreatic cancer study was 0.4% in the erlotinib tablet plus gemcitabine arm and 0.4% in the control arm. In a pharmacokinetic study in 15 patients with moderate hepatic impairment (Child-Pugh B) associated with significant liver tumor burden, 10 of these 15 patients died within 30 days of the last erlotinib tablet dose. One patient died from hepatorenal syndrome, 1 patient died from rapidly progressing liver failure and the remaining 8 patients died from progressive disease.
Six out of the 10 patients who died had baseline total bilirubin > 3 x ULN. Perform periodic liver testing (transaminases, bilirubin, and alkaline phosphatase) during treatment with erlotinib tablets. Increased frequency of monitoring of liver function is required for patients with pre-existing hepatic impairment or biliary obstruction. Withhold erlotinib tablets in patients without pre-existing hepatic impairment for total bilirubin levels greater than 3 times the upper limit of normal or transaminases greater than 5 times the upper limit of normal.
Withhold erlotinib tablets in patients with pre-existing hepatic impairment or biliary obstruction for doubling of bilirubin or tripling of transaminases values over baseline. Discontinue erlotinib tablets in patients whose abnormal liver tests meeting the above criteria do not improve significantly or resolve within three weeks [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) ]
5.4Gastrointestinal Perforation
Gastrointestinal perforation, including fatal cases, can occur with erlotinib tablets treatment. Patients receiving concomitant anti-angiogenic agents, corticosteroids, NSAIDs, or taxane-based chemotherapy, or who have prior history of peptic ulceration or diverticular disease may be at increased risk of perforation [see Adverse Reactions (6.1 , 6.2) ] . The pooled incidence of gastrointestinal perforation in the 3 monotherapy lung cancer studies was 0.2% in the erlotinib tablets arms and 0.1% in the control arms.
The incidence of gastrointestinal perforation in the pancreatic cancer study was 0.4% in the erlotinib tablets plus gemcitabine arm and 0% in the control arm. Permanently discontinue erlotinib tablets in patients who develop gastrointestinal perforation [see Dosage and Administration (2.4) ] .
5.5Bullous and Exfoliative Skin Disorders
Bullous, blistering and exfoliative skin conditions, including cases suggestive of Stevens-Johnson syndrome/toxic epidermal necrolysis, which in some cases were fatal, can, occur with erlotinib tablets treatment [see Adverse Reactions (6.1 , 6.2) ] . The pooled incidence of bullous and exfoliative skin disorders in the 3 monotherapy lung cancer studies was 1.2% in the erlotinib tablets arms and 0% in the control arms.
The incidence of bullous and exfoliative skin disorders in the pancreatic cancer study was 0.4% in the erlotinib tablets plus gemcitabine arm and 0% in the control arm. Discontinue erlotinib tablets treatment if the patient develops severe bullous, blistering or exfoliating conditions [see Dosage and Administration (2.4) ] .
5.6 Cerebrovascular Accident In the pancreatic carcinoma trial, seven patients in the erlotinib tablets/gemcitabine group developed cerebrovascular accidents (incidence: 2.5%). One of these was hemorrhagic and was the only fatal event. In comparison, in the placebo/gemcitabine group there were no cerebrovascular accidents. The pooled incidence of cerebrovascular accident in the 3 monotherapy lung cancer studies was 0.6% in the erlotinib tablets arms and not higher than that observed in the control arms.
5.7Microangiopathic Hemolytic Anemia with Thrombocytopenia
The pooled incidence of microangiopathic hemolytic anemia with thrombocytopenia in the 3 monotherapy lung cancer studies was 0% in the erlotinib tablets arms and 0.1% in the control arms. The incidence of microangiopathic hemolytic anemia with thrombocytopenia in the pancreatic cancer study was 1.4% in the erlotinib tablets plus gemcitabine arm and 0% in the control arm.
5.8Ocular Disorders
Decreased tear production, abnormal eyelash growth, keratoconjunctivitis sicca or keratitis can occur with erlotinib tablets treatment and can lead to corneal perforation or ulceration [see Adverse Reactions (6.1) and (6.2) ] . The pooled incidence of ocular disorders in the 3 monotherapy lung cancer studies was 17.8% in the erlotin
Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA
Interactions
CYP3A4 Inhibitors Co-administration of erlotinib tablets with a strong CYP3A4 inhibitor or a combined CYP3A4 and CYP1A2 inhibitor increased erlotinib exposure. Erlotinib is metabolized primarily by CYP3A4 and to a lesser extent by CYP1A2. Increased erlotinib exposure may increase the risk of exposure-related toxicity [see Clinical Pharmacology (12.3) ] . Avoid co-administering erlotinib tablets with strong CYP3A4 inhibitors (e.g., boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telithromycin, voriconazole, grapefruit or grapefruit juice) or a combined CYP3A4 and CYP1A2 inhibitor (e.g., ciprofloxacin).
Reduce the erlotinib tablets dosage when co-administering with a strong CYP3A4 inhibitor or a combined CYP3A4 and CYP1A2 inhibitor if co-administration is unavoidable [see Dosage and Administration (2.4) ] . CYP3A4 Inducers Pre-treatment with a CYP3A4 inducer prior to erlotinib tablets decreased erlotinib exposure [see Clinical Pharmacology (12.3) ] . Increase the erlotinib tablets dosage if co-administration with CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, rifabutin, rifapentine, phenobarbital and St.
John's wort) is unavoidable [see Dosage and Administration (2.4) ]. CYP1A2 Inducers and Cigarette Smoking Cigarette smoking decreased erlotinib exposure. Avoid smoking tobacco (CYP1A2 inducer) and avoid concomitant use of erlotinib tablets with moderate CYP1A2 inducers (e.g., teriflunomide, rifampin, or phenytoin). Increase the erlotinib tablets dosage in patients that smoke tobacco or when co-administration with moderate CYP1A2 inducers is unavoidable [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) ] .
Drugs the Increase Gastric pH Co-administration of erlotinib tablets with proton pump inhibitors (e.g., omeprazole) and H-2 receptor antagonists (e.g., ranitidine) decreased erlotinib exposure [see Clinical Pharmacology (12.3) ] . For proton pump inhibitors, avoid concomitant use if possible. For H-2 receptor antagonists and antacids, modify the dosing schedule [see Dosage and Administration (2.4) ]. Increasing the dose of erlotinib when co-administered with gastric PH elevating agents is not likely to compensate for the loss of exposure.
Anticoagulants Interaction with coumarin-derived anticoagulants, including warfarin, leading to increased International Normalized Ratio (INR) and bleeding adverse reactions, which in some cases were fatal, have been reported in patients receiving erlotinib tablets. Regularly monitor prothrombin time or INR in patients taking coumarin-derived anticoagulants. Dose modifications of erlotinib tablets are not recommended [see Warnings and Precautions (5.9) and Adverse Reactions (6.1) ] .
CYP3A4 inhibitors or a combined CYP3A4 and CYP1A2 inhibitor increase erlotinib plasma concentrations. Avoid concomitant use. If not possible, reduce erlotinib dose. ( 2.4 , 7 ) CYP3A4 inducers decrease erlotinib plasma concentrations. Avoid concomitant use. If not possible, increase erlotinib dose. ( 2.4 , 7 ) Cigarette smoking and CYP1A2 inducers decrease erlotinib plasma concentrations. Avoid concomitant use. If not possible, increase erlotinib dose.
( 2.4, 7 ) Drugs that increase gastric pH decrease erlotinib plasma concentrations. For proton pump inhibitors avoid concomitant use if possible. For H-2 receptor antagonists, take erlotinib 10 hours after H-2 receptor antagonist dosing. For use with antacids, separate dosing by several hours. ( 2.4 , 7 )
Pregnancy and breastfeeding
8.1Pregnancy Risk Summary Based
on animal data and its mechanism of action, erlotinib tablets can cause fetal harm when administered to a pregnant woman. Limited available data on use of erlotinib tablets in pregnant women are not sufficient to inform a risk of major birth defects or miscarriage. When given during organogenesis, erlotinib administration resulted in embryo-fetal lethality and abortion in rabbits at exposures approximately 3 times the exposure at the recommended human daily dose of 150 mg.
Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data Erlotinib has been shown to cause maternal toxicity resulting in embryo-fetal lethality and abortion in rabbits when given during the period of organogenesis at doses that result in plasma drug concentrations approximately 3 times those achieved at the recommended dose in humans (AUCs at 150 mg daily dose).
During the same period, there was no increase in the incidence of embryo-fetal lethality or abortion in rabbits or rats at doses resulting in exposures approximately equal to those in humans at the recommended daily dose. In an independent fertility study female rats treated with 30 mg/m 2 /day or 60 mg/m 2 /day (0.3 or 0.7 times the recommended daily dose, on a mg/m 2 basis) of erlotinib had an increase in early resorptions that resulted in a decrease in the number of live fetuses.
No teratogenic effects were observed in rabbits or rats dosed with erlotinib during organogenesis at doses up to 600 mg/m 2 /day in the rabbit (3 times the plasma drug concentration seen in humans at 150 mg/day) and up to 60 mg/m 2 /day in the rat (0.7 times the recommended dose of 150 mg/day on a mg/m 2 basis).
Adverse reactions
The following serious adverse reactions, which may include fatalities, are discussed in greater detail in other sections of the labeling: Interstitial Lung Disease (ILD) [see Warnings and Precautions (5.1) ] Renal Failure [see Warnings and Precautions (5.2) ] Hepatotoxicity with or without Hepatic Impairment [see Warnings and Precautions (5.3) ] Gastrointestinal Perforation [see Warnings and Precautions (5.4) ] Bullous and Exfoliative Skin Disorders [see Warnings and Precautions (5.5) ] Cerebrovascular Accident [see Warnings and Precautions (5.6) ] Microangiopathic Hemolytic Anemia with Thrombocytopenia [see Warnings and Precautions (5.7) ] Ocular Disorders [see Warnings and Precautions (5.8) ] Hemorrhage in Patients Taking Warfarin [see Warnings and Precautions (5.9) ] The most common adverse reactions (≥20%) with erlotinib tablets from a pooled analysis in patients with NSCLC across all approved lines of therapy, with and without EGFR mutations, and in patients with pancreatic cancer were rash, diarrhea, anorexia, fatigue, dyspnea, cough, nausea, and vomiting.
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact 1-888-557-1212 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch
6.1Clinical Trials Safety 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. Safety evaluation of erlotinib tablet is based on more than 1200 cancer patients who received erlotinib tablet as monotherapy, more than 300 patients who received erlotinib tablet 100 or 150 mg plus gemcitabine, and 1228 patients who received erlotinib tablet concurrently with other chemotherapies.
The most common adverse reactions with erlotinib tablet are rash and diarrhea usually with onset during the first month of treatment. The incidences of rash and diarrhea from clinical studies of erlotinib tablet for the treatment of NSCLC and pancreatic cancer were 70% for rash and 42% for diarrhea. Non-Small Cell Lung Cancer First-Line Treatment of Patients with EGFR Mutations The most frequent (≥ 30%) adverse reactions in erlotinib tablets-treated patients were diarrhea, asthenia, rash, cough, dyspnea, and decreased appetite.
In erlotinib tablets-treated patients the median time to onset of rash was 15 days and the median time to onset of diarrhea was 32 days. The most frequent Grade 3-4 adverse reactions in erlotinib tablets-treated patients were rash and diarrhea. Dose interruptions or reductions due to adverse reactions occurred in 37% of erlotinib tabletstreated patients, and 14.3% of erlotinib tablets-treated patients discontinued therapy due to adverse reactions.
In erlotinib tablets-treated patients, the most frequently reported adverse reactions leading to dose modification were rash (13%), diarrhea (10%), and asthenia (3.6%). Common adverse reactions in Study 1,occurring in at least 10% of patients who received erlotinib tablets or chemotherapy and an increase in ≥ 5% in the erlotinib tablets-treated group, are graded by National Cancer Institute Common Toxicity Criteria for Adverse Events version 3.0 (NCI-CTCAE v3.0) Grade in Table 1.
The median duration of erlotinib tablets treatment was 9.6 months in Study 1. Table 1: Adverse Reactions with an Incidence Rate ≥ 10% and an Increase of ≥ 5% in the erlotinib tablets-Treated Group (Study 1) Erlotinib Tablets N = 84 Chemotherapy † N = 83 Adverse Reaction All Grades % Grades 3-4 % All Grades % Grades 3-4 % Rash ‡ 85 14 5 0 Diarrhea 62 5 21 1 Cough 48 1 40 0 Dyspnea 45 8 30 4 Dry skin 21 1 2 0 Back pain 19 2 5 0 Chest pain 18 1 12 0 Conjunctivitis 18 0 0 0 Mucosal inflammation 18 1 6 0 Pruritus 16 0 1 0 Paronychia 14 0 0 0 Arthralgia 13 1 6 1 Musculoskeletal pain 11 1 1 0 † Platinum-based chemotherapy (cisplatin or carboplatin with gemcitabine or docetaxel). ‡ Rash as a composite term includes rash, acne, folliculitis, erythema, acneiform dermatitis, dermatitis, palmarplantar erythrodysesthesia syndrome, exfoliative rash, erythematous rash, rash pruritic, skin toxicity, eczema, follicular rash, skin ulcer.
Hepatic Toxicity: One erlotinib-treated patient experienced fatal hepatic failure and four additional patients experienced grade 3-4 liver test abnormalities in Study 1 [see Warnings and Precautions (5.3) ] . Maintenance Treatment Adverse reactions, regardless of causality, that occurred in at least 3% of patients treated with single-agent erlotinib tablets at 150 mg and at least 3% more often than in the placebo group in the randomized maintenance trial (Study 3) are summarized by NCI-CTCAE v3.0 Grade in Table 2.
The most common adverse reactions in patients receiving single-agent erlotinib tablets 150 mg were rash and diarrhea. Grade 3-4 rash and diarrhea occurred in 9% and 2%, respectively, in erlotinib tablets-treated patients. Rash and diarrhea resulted in study discontinuation in 1% and 0.5% of erlotinib tablets-treated patients, respectively. Dose reduction or interruption for rash and diarrhea was needed in 5% and 3% of patients, respectively.
In erlotinib tablets-treated patients the median time to onset of rash was 10 days, and the median time to onset of diarrhea was 15 days. Table 2: NSCLC Maintenance Study: Adverse Reactions Occurring with an Incidence Rate ≥ 10% and an Increase of ≥ 5% in the Single-Agent Erlotinib Tablets Group compared to the Placebo Group (Study 3) Adverse Reaction ERLOTINIB TABLETS N = 433 PLACEBO N = 445 Any Grade % Grade 3% Grade 4% Any Grade % Grade 3% Grade 4% Rash † 60 9 0 9 0 0 Diarrhea 20 2 0 4 0 0 † Rash as a composite term includes: rash, acne, acneiform dermatitis, skin fissures, erythema, papular rash, rash generalized, pruritic rash, skin exfoliation, urticaria, dermatitis, eczema, exfoliative rash, exfoliative dermatitis, furuncle, macular rash, pustular rash, skin hyperpigmentation, skin reaction, skin ulcer.
Liver test abnormalities including ALT elevations were observed at Grade 2 or greater severity in 3% of erlotinib tablets-treated patients and 1% of placebo-treated patients. Grade 2 and above bilirubin elevations were observed in 5% of erlotinib tablets patients and in < 1% in the placebo group [see Dosage and Administration (2.4) and Warnings and Precautions (5.3) ] . Second/Third Line Treatment Adverse reactions, regardless of causality, that occurred in at least 10% of patients treated with single-agent erlotinib tablets at 150 mg and at least 5% more often than in the placebo group in the randomized trial of patients with NSCLC are summarized by NCI-CTC v2.0 Grade in Table 3.
The most common adverse reactions in this patient population were rash and diarrhea. Grade 3-4 rash and diarrhea occurred in 9% and 6%, respectively, in erlotinib tablets -treated patients. Rash and diarrhea each resulted in study discontinuation in 1% of erlotinib tablets -treated patients. Six percent and 1% of patients needed dose reduction for rash and diarrhea, respectively. The median time to onset of rash was 8 days, and the median time to onset of diarrhea was 12 days.
Table 3: NSCLC 2 nd /3 rd Line Study: Adverse Reactions Occurring with an Incidence Rate ≥ 10% and an Increase of ≥ 5% in the Single-Agent Erlotinib Tablets Group Compared to the Placebo Group (Study 4) Adverse Reaction ERLOTINIB TABLETS 150 mg N = 485 PLACEBO N = 242 Any Grade % Grade 3% Grade 4% Any Grade % Grade 3% Grade 4% Rash † 75 8 < 1 17 0 0 Diarrhea 54 6 < 1 18 < 1 0 Anorexia 52 8 1 38 5 < 1 Fatigue 52 14 4 45 16 4 Dyspnea 41 17 1 35 15 11 Nausea 33 3 1 24 2 0 Infection 24 4 0 15 2 0 Stomatitis 17 < 1 0 3 0 0 Pruritus 13 < 1 0 5 0 0 Dry skin 12 0 0 4 0 0 Conjunctivitis 12 < 1 0 2 < 1 0 Keratoconjunctivitis sicca 12 0 0 3 0 0 † Rash as a composite term includes: rash, palmar-plantar erythrodysesthesia syndrome, acne, skin disorder, pigmentation disorder, erythema, skin ulcer, exfoliative derma
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Composition
Active ingredients
ERLOTINIB HYDROCHLORIDE EQ 100MG BASE
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
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