Date of approval.
Date of revision.
Erlotinib Hydrochloride Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic name: Erlotinib Hydrochloride Tablets
English name: Erlotinib Hydrochloride Tablets
Hanyu Pinyin：Yansuan Eluotini Pian
Ingredients
The main ingredient of this product is Erlotinib Hydrochloride.
Chemical name: N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine hydrochloride
Chemical structure formula.
Molecular formula: C22H23N3O4-HCl
Molecular weight: 429.90
Properties
This product is a white film-coated tablet, which appears white after removing the coating.
Indications】
Erlotinib monotherapy is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with sensitive mutations in the epidermal growth factor receptor (EGFR) gene, including first-line therapy, maintenance therapy, or second-line therapy and beyond after at least one prior chemotherapy progression.
The results of two multicenter, randomized, placebo-controlled phase III trials showed that erlotinib in combination with a platinum-containing chemotherapy regimen (carboplatin + paclitaxel; or gemcitabine + cisplatin) did not increase clinical benefit relative to platinum-containing chemotherapy alone as first-line treatment for patients with locally advanced or metastatic NSCLC, and is therefore not recommended for first-line treatment in these conditions.
Specification
0.15g
Dosage]
This product must be used under the supervision of a physician experienced in the use of such drugs.
Patients should be tested for EGFR mutation status before considering this product for first-line treatment or maintenance therapy in patients with locally advanced or metastatic NSCLC.
The recommended dose of erlotinib alone for non-small cell lung cancer is 150 mg/day, taken at least one hour before or two hours after a meal. Continue dosing until disease progression or intolerable toxicities occur. There is no evidence that patients benefit from continued treatment with this product after progression.
Dose Adjustment
Patients experiencing new acute exacerbations or progressive pulmonary symptoms such as dyspnea, cough and fever should have erlotinib therapy suspended for diagnostic evaluation. If the diagnosis is confirmed as ILD (interstitial lung disease), erlotinib should be discontinued and appropriate therapy given (see [Precautions] WARNINGS – Pulmonary Toxicity). Erlotinib should be discontinued in patients with hepatic failure or gastrointestinal perforation. Erlotinib should be interrupted or discontinued in patients who are dehydrated and at risk of renal failure, in patients with severe maculopapular, blistering, or exfoliative skin disease, and in patients with acute/exacerbating eye disease (see [Precautions]).
Diarrhea is usually controlled with loperamide. Patients with severe diarrhea who are ineffective with loperamide or who become dehydrated require dose reduction and temporary discontinuation of therapy. Patients with severe skin reactions also require dose reduction and temporary discontinuation of therapy.
If dose reduction is necessary, erlotinib should be reduced by 50 mg at a time.
Dose reduction should be considered with concomitant use of strong CYP3A4 inhibitors such as atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, vinblastine (TAO), voriconazole, or grapefruit or grapefruit juice, as otherwise serious adverse reactions can occur. Similarly, patients using concomitant CYP3A4 and CYP1A2 co-inhibitors (e.g., ciprofloxacin) should have their erlotinib dosage reduced if serious adverse reactions occur (see [Drug Interactions]).
The use of the CYP3A4 inducer rifampicin prior to treatment may reduce erlotinib AUC by 2/3-4/5. Other alternative drugs without CYP3A4-inducing activity should be considered. If no alternative drug is available, doses of erlotinib higher than 150 mg may be considered, but safety should be closely monitored. The maximum investigational dose of erlotinib in combination with rifampin is 450 mg. If the dose of erlotinib is increased, erlotinib should be rapidly reduced again to the initial dose when rifampin or other inducers are discontinued. Other CYP3A4 inducers include, but are not limited to, rifabutin, rifapentine, phenytoin, carbamazepine, phenobarbital, and St. John’s Wort, which should also be avoided if possible (see [Precautions] and [Drug Interactions]).
Erlotinib is metabolized by the liver and secreted by the biliary tract. Although exposure to erlotinib in patients with moderate hepatic impairment (Child-Pugh classification 7-9) is similar to that of patients with normal hepatic function, erlotinib should be used with caution in patients with hepatic impairment. Erlotinib should be used with caution in patients with total bilirubin > 3 x ULN. In the case of abnormal pretreatment tests, erlotinib should be interrupted or discontinued if there are severe changes in liver function, such as doubling of total bilirubin and/or a threefold increase in transaminases. In the case of persistent worsening of liver function abnormalities on examination, dose interruption and/or reduction should be considered before reaching severe abnormalities along with increased frequency of liver function test monitoring. If total bilirubin >3 x ULN and/or transaminases >5 x ULN are normal on pretreatment testing, interrupt or discontinue erlotinib (see [Precautions] and [Adverse Reactions]).
Efficacy and safety studies in patients with renal impairment (serum creatinine concentration >1.5 x ULN) have not been performed. Based on pharmacokinetic data, no dose adjustment is required in patients with mild or moderate renal impairment (see [Pharmacokinetics]). Erlotinib is not recommended for patients with severe renal impairment.
Smoking has been shown to result in a 50-60% reduction in erlotinib exposure. The maximum tolerated dose of erlotinib in patients with NSCLC who are smoking is 300 mg. In patients who continue to smoke, the 300 mg dose has not shown improved efficacy in second-line therapy after chemotherapy failure compared with the recommended 150 mg dose. (See [Drug Interactions] and [Pharmacokinetics] Special Populations).
Adverse Reactions]
Because of the widely varying conditions under which clinical trials are conducted, it is not possible to directly compare the incidence of adverse reactions in clinical trials of one drug with that of another, and may not reflect the incidence observed in clinical practice.
The safety assessment of erlotinib was based on data from more than 1,500 patients who received at least one dose of 150 mg erlotinib monotherapy and more than 300 patients who received erlotinib 100 mg or 150 mg in combination with gemcitabine, and 1,228 patients who received erlotinib in combination with chemotherapy.
The adverse reactions (ADRs) reported from clinical trials of erlotinib alone or in combination with chemotherapy are summarized below. The ADRs listed in the table below are those that occurred at least 10% (in the erlotinib group) and were higher (³3%) than in the control group. Frequency categories include very common (≥1/10), common (≥1/100,<1/10), occasional (≥1/1000,<1/100), rare (≥1/10,000,<1/1000), and very rare (<1/10,000).
Serious adverse reactions, including fatal events, have been reported in patients taking erlotinib for NSCLC and other advanced solid tumors (see [PRECAUTIONS] WARNINGS – Pulmonary Toxicity and [DOSAGE] DOSE ADJUSTMENT).
NSCLC-erlotinib monotherapy
First-line treatment of NSCLC with EGFR-sensitive mutations
The safety of first-line treatment with this product was evaluated in an open randomized controlled phase III study ML20650 (EURTAC) in 75 patients with NSCLC with EGFR mutations in 154 patients, and no new safety signals were identified.
In study ML20650, the most common adverse reactions in patients treated with this product were rash and diarrhea (80% and 57%, respectively, all grades), mostly grade 1 or 2, which were controlled without intervention. the incidence of grade 3 rash and diarrhea was 9% and 4%, respectively. No grade 4 rash or diarrhea was seen. The product was discontinued in 1% of patients due to rash or diarrhea, respectively. Dose adjustment (suspension or reduction) was required in 11% and 7% of patients who experienced rash or diarrhea, respectively.
YO25121 (ENSURE) is a multicenter, open, randomized, controlled phase III clinical study in Asian patients comparing the efficacy and safety of erlotinib with gemcitabine/cisplatin as first-line treatment for advanced (stage IIIB/IV) NSCLC with EGFR gene-sensitive mutations, evaluating the safety of 110 erlotinib-treated patients with known safety profile of erlotinib, and no new safety signals were identified.
The most common AEs in the erlotinib group in this study were rash (67.3%), diarrhea (40.9%), and nail infection (10.9%), with most rashes being grade 1 or 2 and 7 patients (6.4%) presenting with a grade 3 rash. Most of the diarrhea was grade 1 or 2, 2 patients had grade 3 diarrhea, and there was no grade 4 or 5 diarrhea. One case (0.9%) of interstitial pneumonia was observed in the erlotinib-treated group. Elevated alanine aminotransferase (ALT) of 9.1% , aspartate aminotransferase (AST) of 5.5% and bilirubin of 6.4% were reported in the erlotinib group, most of which were grade 1 or 2.
Table 1 Adverse events with higher incidence (≥3%) and ≥10% incidence in the erlotinib group compared with the chemotherapy group in the ENSURE study
Erlotinib group N = 110 Chemotherapy group N = 104 MedDRA
Preferred Term NCI-CTC Grading NCI-CTC Grading All Grades % Grade 3 % Grade 4 % All Grades % Grade 3 % Grade 4 % Rash 67.36.4010.61.00 Diarrhea 40.91.809.61.00 Nail fungus 10.90.90000 The most common serious adverse events (SAEs) in the erlotinib group (at least 2 patients) were dyspnea (3 patients; 2.7%), pleural effusion, upper gastrointestinal bleeding, and bone pain (occurred in 2 patients [1.8%] each).
In another randomized, controlled, open phase III trial (MO20981, OPTIMAL) conducted in 23 centers in China, the efficacy of erlotinib alone was compared with gemcitabine + carboplatin combination chemotherapy in patients with unresectable stage IIIB (T4 pleural effusion) or stage IV NSCLC with EGFR mutations in primary care. The safety evaluation of 83 patients treated with erlotinib was consistent with the known safety profile of erlotinib, and no new safety signals were identified.
The incidence of adverse reactions in this study was 88.0% (73/83) in the erlotinib group and 98.6% (71/72) in the chemotherapy group. The vast majority of these were grade 1 to 2 adverse reactions in the erlotinib group, with few grade 3 to 4 adverse reactions, accounting for 12.0% (10/83), including 2 cases of rash (2.4%) and others including abnormal liver function tests (elevated ALT/AST, increased liver enzymes, elevated transaminases, and elevated blood bilirubin), elevated white blood cell count, diarrhea, hematuria, and oral ulcers in 1 case each (1.2% each) . Grade 3 to 4 adverse reactions in the chemotherapy group accounted for 65.3% (47/72), the most common being abnormal laboratory tests such as decreased neutrophil count, decreased platelet count, decreased white blood cell count and decreased hemoglobin (11.1 to 41.7%).
There were 2 serious adverse reactions in the erlotinib group (2.4%), all of which were abnormal liver function. There were 10 cases (13.9%) of serious adverse reactions in the gemcitabine + carboplatin group, which were 7 cases of decreased platelets and 1 case each of neutropenia, death and abnormal liver function.
Maintenance therapy for NSCLC
A total of 1532 patients with relapsed or metastatic advanced NSCLC in two double-blind, randomized, placebo-controlled phase III studies, BO18192 (SATURN) and BO25460 (IUNO), received erlotinib 150 mg once daily or placebo after receiving first-line standard platinum-based chemotherapy and continued until disease progression, unacceptable toxicity or death events. No new safety signals were identified. The most frequent adverse reactions reported in the erlotinib treatment group were rash and diarrhea (see Table 2.). No grade 4 rash or diarrhea was observed in any of the studies. The percentages of patients discontinuing erlotinib because of rash and diarrhea were 1% and <1%, respectively, in study BO18192, whereas no patients discontinued treatment because of rash or diarrhea in study BO25460. The percentages of patients requiring dose adjustment (interruption or reduction) because of rash and diarrhea were 8.3% and 3% in study BO18192 and 5.6% and 2.8%, respectively, in study BO25460.
Table 2 List of the most common adverse drug reactions in studies BO18192 (SATURN) and BO25460 (IUNO)
BO18192 (SATURN)*BO25460 (IUNO)*MedDRA Preferred term Erlotinib
n=433 placebo
n=445 Erlotinib
n=322 placebo
n=319 %%%% Rash, any grade 49.25.839.410.0 Grade 3 6.005.01.6 Diarrhea, any grade 20.34.524.24.4 Grade 3 1.802.50.3 *Safety Analysis Population
In the maintenance therapy study, patients receiving erlotinib monotherapy developed abnormal liver function tests (including elevated ALT, AST and bilirubin). Grade 2 (> 2.5 – 5.0 x ULN) ALT elevations occurred in 2% and 1% of patients treated in the erlotinib and placebo groups, respectively, and grade 3 (> 5.0 – 20.0 x ULN) ALT elevations occurred in 1% and 0% of patients treated in the erlotinib and placebo groups, respectively. Grade 2 (>1.5 – 3.0 x ULN) and grade 3 (>3.0 – 10.0 x ULN) bilirubin elevations were seen in 4% and <1% of patients in the erlotinib-treated group, respectively, compared to both events in the placebo group <1%. Erlotinib administration should be interrupted or discontinued if severe changes in liver function occur (see [DOSAGE]).
Second/third-line therapy for NSCLC
In a randomized, double-blind, placebo-controlled phase III study (BR.21), 731 patients with locally advanced or metastatic NSCLC who had failed at least one prior chemotherapy regimen were randomized in a 2:1 ratio to receive once-daily oral erlotinib 150 mg or placebo until disease progression or unacceptable toxicities.
The most common adverse reactions were rash and diarrhea (any grade, 75 % and 54 %, respectively). The extent was mostly grade 1 or 2, and control was obtained without intervention. The incidence of grade 3/4 rash and diarrhea in erlotinib-treated patients was 9 % and 6 %, respectively. The percentage of erlotinib-treated patients who discontinued the trial due to either rash or diarrhea was 1%. The median time to rash in the BR.21 study was 8 days and the median time to diarrhea was 12 days.
Table 3 Adverse reactions with higher incidence (≥5%) and ≥10% incidence in the erlotinib group compared to the placebo group in the BR.21 study
Erlotinib 150 mg group N=485 Placebo group N=242 Adverse drug reactions NCI-CTC classification NCI-CTC classification All classifications % Grade 3 % Grade 4 % All classifications % Grade 3 % Grade 4 % Rash* 758<11700 Diarrhea 556<118<10 Anorexia 5281385<1 Fatigue 5214445164 dyspnea411711351511 nausea33302420 infection24401520 oral mucositis17<10300 pruritus13<10500 dry skin1200400 conjunctivitis12<102<10 dry keratoconjunctivitis1200300* rash is a compound term that includes rash, painful palmoplantar redness and swelling syndrome, acne, skin disorders, pigmentary disorders, erythema, skin ulcers, exfoliative dermatitis, papules, skin desquamation.
Abnormal liver function tests (including elevated ALT, AST and bilirubin) were observed in patients with NSCLC treated with erlotinib 150 mg monotherapy. Elevations were primarily transient or associated with liver metastases. Grade 2 ALT elevations (>2.5-5.0 times the upper limit of normal) were seen in 4% and <1% of erlotinib- and placebo-treated patients, respectively. Grade 3 ALT elevations (>5.0-20.0 times the upper limit of normal) were not seen in erlotinib-treated patients. Consider dose reduction or suspension of therapy for severe liver function abnormalities (see [DOSAGE] Dose Adjustment).
In an interim analysis of a single-arm, uncontrolled international multicenter clinical study (TRUST) of erlotinib monotherapy in advanced NSCLC, safety data from 6578 patients were summarized and no new safety signals were identified. The incidence of erlotinib treatment-related rash was 71%, with a grade 3/4 rash of 12%. The incidence of serious adverse reactions with erlotinib was 4%. Five percent of patients discontinued erlotinib treatment early because of intolerable adverse effects; among 509 enrolled Chinese patients, the incidence of rash was 84%, and the incidence of grade 3/4 rash was 4%. Only 3 (<1%) patients experienced treatment-related serious adverse reactions to erlotinib treatment. 6 (1%) patients discontinued erlotinib treatment early due to adverse reactions.
Pancreatic cancer – Erlotinib in combination with gemcitabine chemotherapy
In a controlled clinical trial (PA.3), 569 patients with locally advanced inoperable resectable or metastatic pancreatic cancer were randomized in a 1:1 ratio to receive erlotinib (100 mg or 150 mg) or placebo in combination with gemcitabine IV (1000 mg/m2, cycle 1 – days 1, 8, 15, 22, (8-week cycles on days 29, 36 and 43; 4-week cycles on days 1, 8 and 15 in Cycle 2 and later cycles). Erlotinib was administered orally daily until disease progression or unacceptable toxicity. The primary endpoint was survival, and the secondary endpoints were remission rate and progression-free survival. Time to remission was also observed. A total of 285 patients were treated with erlotinib in combination with gemcitabine (261 patients in the 100 mg group and 24 patients in the 150 mg group) and 284 patients received gemcitabine plus placebo (260 patients in the 100 mg group and 24 patients in the 150 mg group). The number of patients receiving 150 mg erlotinib was too small to draw any conclusions.
The most common adverse reactions among patients with pancreatic cancer treated with 100 mg erlotinib + gemcitabine were malaise, rash, nausea, loss of appetite, and diarrhea. In the erlotinib + gemcitabine treatment group, the incidence of grade 3/4 rash and diarrhea in treated patients was 5% each, with a median duration of occurrence of 10 and 15 days, respectively, each resulting in dose reductions in 2% of patients and discontinuation in no more than 1% of patients.
The incidence of specific adverse reactions, including rash, was higher in the 150 mg group (23 patients), to the point where dose reductions or discontinuations were more frequent.
Table 4 lists the higher incidence (≥5%) and incidence of ≥10% adverse reactions in patients in the 100 mg erlotinib + gemcitabine treatment group compared with the placebo group in randomized clinical trials in patients with pancreatic cancer, without regard to causality, graded according to the NCI-CTC.
Table 4 Adverse reactions with higher incidence (≥5%) and incidence ≥10% in the erlotinib group compared with the placebo group in the PA.3 study
Adverse reactions Erlotinib + Gemcitabine
1000 mg/m2 IV
N=259 placebo + gemcitabine
1000 mg/m2 IV
N=256 Any Grade 3 Grade 4 Any Grade 3 Grade 4 %%%%%% rash†70503010 diarrhea485<13620 weight loss392029<10 infection*391333092 fever36303040 oral mucositis22<101200 depression192014<10 cough 16001100Headache15<101000* Infection is a composite term that includes infections with unspecified causative agents and bacterial infections (including chlamydia, rickettsia, mycobacteria, and mycoplasma), parasites (including helminths, ectoparasites, and protozoa), viruses, and fungal infectious diseases.
† Rash is a compound term that includes rash, palmoplantar erythema and pain syndrome, pigmentary disorders, acneiform dermatitis, folliculitis, photoallergic reactions, Stevens-Johnson syndrome, urticaria, erythema, skin disorders, and skin ulcers.
In the pancreatic cancer clinical trial, deep vein thrombosis occurred in 10 patients in the erlotinib/gicitabine arm (incidence of 4%). The overall incidence of grade 3 or 4 thrombotic events, including DVT, was similar in the two treatment groups: 11% in the erlotinib + gemcitabine group and 9% in the placebo + gemcitabine group.
No difference in grade 3 or 4 hematologic laboratory toxicity was seen in the erlotinib + gemcitabine group compared with the placebo + gemcitabine group.
Serious adverse reactions (≥ NCI-CTC grade 3) that occurred in less than 5% of the erlotinib + gemcitabine group included syncope, arrhythmia, intestinal obstruction, pancreatitis, hemolytic anemia including microvascular hemolytic anemia due to thrombocytopenia, myocardial infarction/myocardial ischemia, cerebrovascular accidents including cerebral hemorrhage, and renal insufficiency (see [Caution] warning).
Abnormal liver function tests (including elevated ALT, AST, and bilirubin) were observed in patients with pancreatic cancer treated with erlotinib + gemcitabine. The most severe grade of liver function abnormalities that occurred with NCI-CTC are listed in Table 5. If changes in liver function are severe, reduction in erlotinib dosage or discontinuation should be considered (see [Dosage] Dose Adjustment section).
Table 5 Abnormal liver function tests (most severe NCI-CTC grade) in patients with pancreatic cancer: 100 mg group
Erlotinib + Gemcitabine
1000 mg/m2 IV
N=259 placebo + gemcitabine
1000 mg/m2IV
N=256 NCI CTC grading NCI CTC grading Grade 2 Grade 3 Grade 4 Grade 2 Grade 3 Grade 4 Bilirubin 17%10%<1%11%10%3% ALT31%13%<1%22%9%0% AST24%10%<1%19%9%0%
Additional Observational Information (based on data from all clinical studies)
The following adverse reactions were observed in patients receiving erlotinib 150 mg as monotherapy or erlotinib 100 mg or 150 mg in combination with gemcitabine.
The very common adverse reactions are shown in Table 1, Table 2, Table 3 and Table 4, and the classification of other frequency adverse reactions is summarized below.
Gastrointestinal abnormalities.
Gastrointestinal perforation has been reported in the erlotinib treatment group, but is rare (less than 1%), with some cases producing fatal consequences (see [Precautions]).
Gastrointestinal bleeding has been commonly reported (including some deaths), some associated with concomitant warfarin (see [Precautions] International Normalized Ratio (INR) elevation and possible partial bleeding) and others with concomitant NSAIDs. these reports include bleeding from peptic ulcers (gastritis, gastric and duodenal ulcers), vomiting blood, blood in the stool, black stool syndrome, and possible colitis Bleeding (see [Precautions]).
Abnormal renal function
Reports of acute renal failure or renal insufficiency, including death, with or without hypokalemia (see [Precautions])
Abnormal liver function
Abnormal liver function tests (including elevated ALT, AST, and bilirubin) are common in clinical trials of erlotinib and were common in PA3 studies of combination chemotherapy. Most are mild to moderate, transient or associated with liver metastases. Rare cases of liver failure (including death) have been reported during erlotinib use. Confounding factors include pre-existing liver disease or co-administration of hepatotoxic drugs.
Eye disease
Very rare reports of corneal ulceration or perforation have been reported in patients treated with erlotinib.
Keratitis and conjunctivitis are common with erlotinib treatment. Eyelash growth abnormalities include: inward eyelash growth, excessive eyelash growth, and thickening of the eyelashes (see [Precautions]).
Airway, chest and mediastinal abnormalities
Severe interstitial lung disease (ILD-like events including death) has been reported in patients treated with erlotinib for NSCLC and other progressive solid tumors (see [Precautions]).
Epistaxis is common in trials of NSCLC and pancreatic cancer.
Skin and subcutaneous tissue abnormalities
The most commonly reported adverse reaction in patients treated with erlotinib is rash, which generally presents as mild to moderate erythema and pustular papules, most often occurring or worsening on sun-exposed areas of the body. For patients who are to be exposed to the sun, protective clothing and/or sunscreen (e.g., containing minerals) is recommended. Acne vulgaris, acne-like dermatitis and folliculitis are common, mostly mild to moderate and non-severe. Skin cracking is commonly reported, mostly non-serious, mostly associated with rashes and dry skin. Other mild skin reactions such as hyperpigmentation have been observed, but are occasional (less than 1%).
Herpetic, blistering, and exfoliative skin changes have been reported, including the very rare Stevens-Johnson syndrome/neutropenic epidermal necrolysis, which in some cases is fatal (see [Precautions]).
Other hair and nail changes have been reported in clinical trials and are usually not severe, e.g., common nail fungus, occasional hirsutism, eyelash/eyebrow changes, and brittle and loose nails.
Overall, there were no significant differences in the safety of erlotinib between women and men and between younger and older adults over 65 years of age, either as monotherapy or in combination with gemcitabine, or between Caucasian and Asian patients (see [Precautions] and [Geriatric Use]).
Post-marketing Experience
The following adverse reactions were observed after the launch of erlotinib. Because these adverse reactions were spontaneously reported from an uncertain sample size, their frequency and drug causation cannot be reliably estimated.
Skin and subcutaneous tissue abnormalities :
Hair and nail changes, usually not severe, have been reported occasionally in post-marketing surveillance, e.g., hirsutism, eyelash/eyebrow changes, nail fungus, and brittle and loose nails.
Skin conditions such as maculoplasia, blistering, and epidermal peeling have also been reported, suggesting Stevens-Johnson syndrome/necrotizing epidermolysis bullosa.
Gastrointestinal abnormalities
Gastrointestinal perforation
Liver abnormalities
Liver failure has been reported in patients treated with erlotinib monotherapy or in combination with chemotherapy.
Musculoskeletal and connective tissue abnormalities
Myopathy, including rhabdomyolysis, has occurred in combination with statin therapy.
Ophthalmic abnormalities
Uveitis has been reported in post-marketing surveillance.
Contraindications
Contraindicated in patients with hypersensitivity to this product and its ingredients.
Precautions]
This product must be used under the supervision of a physician experienced in the use of such drugs.
When considering this product for the treatment of patients with advanced or metastatic NSCLC, it is recommended that all patients be evaluated for EGFR mutations and that well-validated and reliable methods be used to avoid false-negative or false-positive test results. Note that the safety and efficacy of erlotinib as first-line therapy has not been evaluated in patients with metastatic NSCLC whose tumors have EGFR mutations other than exon 19 deletions or exon 21 (L858R) substitutions (see [Clinical Trials]).
Warnings
Pulmonary Toxicity
Serious interstitial lung disease-like events, including fatalities, have occasionally been reported in patients treated with erlotinib in NSCLC or other solid tumors. In the erlotinib monotherapy NSCLC trial (see [Clinical Trials]), the incidence of interstitial lung disease-like events in the maintenance treatment study was 0.7% and 0% in the erlotinib and placebo groups, respectively, and the incidence of interstitial lung disease-like events in the second/third-line treatment study (0.8%) was the same in the erlotinib and placebo groups. meta-analysis of randomized controlled clinical trials in NSCLC The results showed that the incidence of interstitial lung disease-like events was 0.9% in the erlotinib group and 0.4% in the control group. In the treatment of pancreatic cancer trial – in combination with gemcitabine (see [Clinical Trials]), the incidence of interstitial lung disease-like events was 2.5% in the erlotinib + gemcitabine group and 0.4% in the placebo + gemcitabine group.
Diagnoses reported in patients with suspected interstitial lung disease-like events included pneumonia, radiation pneumonia, allergic pneumonia, interstitial pneumonia, interstitial lung disease, occlusive fine bronchitis, pulmonary fibrosis, acute respiratory distress syndrome, pulmonary infiltrates, and alveolitis. Symptoms appeared between 5 days and 9 months (median time 39 days) after taking erlotinib. Most cases were combined with other factors causing interstitial lung disease, such as concurrent or prior chemotherapy, prior radiation therapy, preexisting parenchymal lung disease, metastatic lung disease, or lung infection.
Temporarily discontinue erlotinib therapy at the time of diagnostic evaluation once a new acute episode or progressive unexplained pulmonary symptoms such as dyspnea, cough and fever have developed. Once the diagnosis of ILD (interstitial lung disease) is confirmed, erlotinib therapy should be discontinued and appropriate treatment given if necessary (see [Adverse Reactions] and [Dosage]).
Diarrhea, dehydration, electrolyte imbalance and renal failure
Diarrhea may occur in patients receiving erlotinib and moderate or severe diarrhea should be treated with loperamide. Some patients may require dose reduction. For severe or persistent dehydration-related diarrhea, nausea, anorexia, or vomiting, patients need to discontinue the drug and take appropriate treatment for dehydration (see [ADVERSE REACTIONS]). Hepatorenal syndrome, acute renal failure (including death), and renal insufficiency have been reported in patients treated with erlotinib. Some are caused by baseline liver injury and some are associated with dehydration due to diarrhea, vomiting, and/or anorexia or combination chemotherapy.
Hypokalemia and renal failure (including fatal cases) have been reported rarely, some secondary to dehydration due to diarrhea, vomiting, and/or anorexia, and some in combination with chemotherapeutic agents.
In three studies of monotherapy for lung cancer, the overall incidence of severe renal impairment was 0.5% in the erlotinib group and 0.8% in the control group. In the pancreatic cancer study, the incidence of renal damage was 1.4% in the erlotinib plus gemcitabine group and 0.4% in the control group. Erlotinib was suspended until the nephrotoxicity subsided in patients who developed severe renal impairment.
In patients who develop severe or persistent diarrhea or even dehydration, especially in the group of patients with high risk factors (e.g., receiving concurrent chemotherapy, having other symptoms or diseases, or having other underlying factors including older age), erlotinib therapy should be interrupted and appropriate measures should be taken to rehydrate the patient intravenously. Renal function and blood electrolytes, including potassium, should be monitored along with rehydration in patients who are dehydrated, and regular monitoring of renal function and serum electrolytes in patients at risk for dehydration is recommended (see [Adverse Reactions]).
Myocardial infarction/myocardial ischemia
In the pancreatic cancer clinical trial, 6 patients (incidence 2.3%) in the erlotinib/gicitabine arm experienced myocardial infarction/myocardial ischemia, with 1 patient dying due to myocardial infarction. In contrast, 3 patients in the placebo/gicitabine group had myocardial infarction (incidence 1.2%), including 1 death due to myocardial infarction.
Cerebrovascular accidents
In the pancreatic cancer clinical trial, 6 patients in the erlotinib/gicitabine arm (incidence 2.3%) had a cerebrovascular accident, with one bleed, the only fatal event. In contrast, there were no cerebrovascular accidents in the placebo/gicitabine group.
Microvascular hemolytic anemia due to thrombocytopenia
In the pancreatic cancer clinical trial, microvascular hemolytic anemia due to thrombocytopenia occurred in 2 patients (incidence 0.8%) in the erlotinib/gicitabine arm. Both patients were on both erlotinib and gemcitabine. In contrast, no thrombocytopenia-induced microvascular hemolytic anemia occurred in the placebo/gicitabine group.
Hepatitis, Liver Failure
Rare cases of hepatic failure, including death, were reported during erlotinib use. Confounding factors include previous liver disease or co-administration of hepatotoxic drugs. Therefore, regular liver function tests should be performed in such patients. Erlotinib should be discontinued in those who develop severe liver function abnormalities. In the event of persistent worsening of liver function abnormalities on examination, dose interruption and/or reduction along with increased frequency of liver function test monitoring should be considered. If total bilirubin >3 × ULN and/or transaminases >5 × ULN are normal on pretreatment testing, erlotinib should be discontinued or stopped (see [Adverse Reactions] and [Dosage]).
Patients with abnormal liver function and liver injury
Both ex vivo and in vivo studies have demonstrated that erlotinib is primarily cleared in the liver. Therefore, exposure to erlotinib is increased in patients with abnormal liver function (see [Pharmacokinetics] Special Populations – Patients with Abnormal Liver Function and [Dosage] Dose Adjustment).
In a pharmacokinetic study in patients with moderate liver injury (Child-Pugh B) (associated with significant hepatic tumor load), 10 of 15 patients died during treatment or within 30 days of the last dose of erlotinib. 1 patient died of hepatorenal syndrome, 1 patient died of rapidly progressive liver failure, and the remaining 8 died of progressive disease. 8 of the 10 patients who died had a baseline total This indicates severe liver injury and therefore erlotinib should be used with caution in patients with a total bilirubin> 3 × ULN. Patients with liver injury (total bilirubin> ULN or Child-Pugh A, B and C) should be monitored closely during erlotinib treatment. In cases of abnormal pretreatment tests, erlotinib should be interrupted or discontinued if there are severe changes in liver function with doubling of total bilirubin and/or tripling of transaminases (see [DOSAGE]).
Gastrointestinal Perforation
Patients receiving erlotinib have an increased but uncommon risk of gastrointestinal perforation (with fatal consequences in some cases). The risk is higher in patients on concomitant anti-angiogenic agents, corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs), and/or paclitaxel-based chemotherapy, or with a history of prior peptic ulcer or diverticular disease. Erlotinib should be permanently discontinued in patients who develop gastrointestinal perforation (see [Adverse Reactions]).
Herpetic or exfoliative skin changes
Herpetic, blistering, and exfoliative skin conditions, including the very rare Stevens-Johnson syndrome/neutropenic epidermolysis bullosa, have been reported, in some cases fatal (see [ADVERSE REACTIONS]). Erlotinib should be interrupted or discontinued if the patient develops severe herpetic, blistering, and exfoliative skin symptoms.
Eye disease
There have been very rare reports of corneal perforation or corneal ulceration with erlotinib treatment. Other ocular abnormalities observed include abnormal eyelash growth, dry keratoconjunctivitis or herpetic keratitis, which are also risk factors for the development of corneal perforation/ulceration. Erlotinib should be interrupted or discontinued if patients develop acute ophthalmic abnormalities or worsen, for example, eye pain (see [ADVERSE REACTIONS]).
Interactions
Clinically significant drug-drug interactions may occur with erlotinib (see [Drug Interactions]).
Elevated International Normalized Ratio and Bleeding Possible
Interactions with coumarin-based anticoagulants, including warfarin, have been reported in patients treated with this product, resulting in elevated international normalized ratios (INR) and increased bleeding events, in some cases with fatal consequences. Changes in clotting time and INR should be monitored regularly in patients using coumarin-based anticoagulants.
The tablets contain lactose and therefore should not be used in patients with the rare genetic disorder galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.
Effects on driving and machine handling ability
Erlotinib has no or little effect on the ability to drive and operate machinery.
[Use in Pregnant and Lactating Women].
Adequate, controlled studies of erlotinib have not been performed in pregnant women. Maternal toxicity resulting in embryonic/fetal death and abortion occurred in rabbits during the organogenesis phase when plasma concentrations of erlotinib reached three times the human plasma concentration at the time of 150 mg daily dosing. Female rats receiving erlotinib at doses equivalent to 0.3 or 0.7 times the clinical dose of 150 mg (based on mg/m2) prior to mating through the first week of gestation can cause early absorption resulting in a decrease in the number of viable fetuses. The potential risk to humans is unknown. Women of childbearing potential should avoid pregnancy while taking erlotinib. Adequate contraception should be used during treatment and for at least 2 weeks after completion of treatment. Pregnant women should continue treatment only if the benefit to the mother is considered to outweigh the risk to the fetus. If erlotinib is used during pregnancy, patients should be aware of the potential harm to the fetus and the potential for miscarriage.
It is not known whether erlotinib is secreted in human breast milk. No studies have been conducted to assess the effect of erlotinib on milk production or whether it is present in breast milk. Because many drugs can be secreted into human milk and the effect of erlotinib on breast-fed infants is not known, mothers treated with erlotinib are not advised to breast-feed during dosing and for at least 2 weeks after the last dose.
[Pediatric Dosage].
The efficacy and safety of erlotinib has not been established in patients under 18 years of age for the approved indications.
Geriatric Use]
Maintenance therapy for NSCLC
Approximately 66% of all patients enrolled in randomized NSCLC maintenance therapy trials were younger than 65 years of age and 34% were equal to or older than 65 years of age. the risk ratio for overall survival was 0.78 (95% CI: 0.65, 0.95) for patients younger than 65 years of age and 0.88 (95% CI: 0.68, 1.15) for patients 65 years of age or older.
Second/third-line treatment for NSCLC
Sixty-two percent of the total population enrolled in randomized trials for NSCLC were younger than 65 years of age, while 38% of patients were 65 years of age or older. Survival benefit was achieved in both age groups (see [Clinical Trials]).
[Drug Interactions].
Interaction studies have been conducted in adults only.
In vitro studies have found erlotinib to be a potent inhibitor of CYP1A1, a moderate inhibitor of CYP3A4 and CYP2C8, and a strong inhibitor of UGT1A1-induced glucosylation.
Due to the very limited expression of CYP1A1 in human tissues, there is no way to obtain the physiological relevance of a strong inhibitor of CYP 1Al.
The inhibition of glucosylation may lead to interactions with some UGT1A1 substrate analogs that can only be cleared by this pathway. Serum bilirubin concentrations may be elevated in patients with low levels of UGT1A1 expression or with genetic glucosylation disorders such as Gilbert’s disease and must be used with caution.
Erlotinib is metabolized by the liver, primarily via CYP3A4 and to a lesser extent via CYP1A2 and the pulmonary isoenzyme CYP1A1. Any drug metabolized by these enzymes or inhibitors or inducers of the enzymes have the potential to interact with erlotinib.
Strong inhibitors of CYP3A4 can decrease erlotinib metabolism and increase its blood levels. Compared to erlotinib alone, ketoconazole (200 mg taken twice daily for 5 days) resulted in an increase in AUC (mean AUC increased by 86%) and a 69% increase in Cmax of erlotinib by inhibiting CYP3A4 metabolic activity. The combination of erlotinib with the CYP3A4 and CYP1A2 inhibitor ciprofloxacin increased the AUC and Cmax of erlotinib by 39% and 17%, respectively, and the AUC and Cmax of the active metabolite by approximately 60% and 48%, respectively, and the clinical relevance of this increased exposure is not yet clear. Erlotinib should be used with caution in combination with ciprofloxacin or potent CYP1A2 inhibitors such as fluvoxamine. Therefore, care should be taken when combining erlotinib with strong CYP3A4 inhibitors or combined CYP3A4 /CYP1A2 inhibitors, and the erlotinib dose should be reduced if toxic effects are observed.
CYP3A4 strong inducers can increase the metabolism of erlotinib and significantly reduce erlotinib blood levels. After administration of 150 mg erlotinib, rifampicin (600 mg taken once daily for 7 days) resulted in a 69% reduction in the mean AUC of erlotinib by inducing CYP3A4 metabolic activity compared to erlotinib alone.
If rifampicin had been used prior to treatment or was used during treatment, the mean AUC of erlotinib after a single dose of 450 mg was 57.5% of that after a single dose of 150 mg erlotinib when not treated with rifampicin. If possible, treatment with other agents that are not strongly CYP3A4-inducible should be chosen. For patients requiring treatment with erlotinib + a strong CYP3A4 inducer (e.g., rifampin), a dose increase to 300 mg should be considered with close monitoring of drug safety (see [Precautions]), and a further dose increase to 450 mg may be considered if well tolerated for more than 2 weeks, with close monitoring of drug safety. Higher doses have not been studied under this condition. Exposure may also be reduced when combined with other induction agents such as phenytoin, carbamazepine, barbiturates, or St. Johns Wort, and special care should be taken when combining erlotinib with these active agents. Where possible, other therapeutic agents without potent CYP3A4-inducing activity may be considered.
Erlotinib pretreatment or co-administration has no effect on the clearance of the typical CYP3A4 substrates midazolam and erythromycin. Therefore, significant interactions with clearance of other CYP3A4 substrates are also unlikely to occur. The oral utilization of midazolam appeared to be reduced by 24%, but this was not due to an effect of CYP3A4 activity. In another clinical trial, erlotinib had no effect on its pharmacokinetics when combined with the CYP3A4/2C8 substrate paclitaxel. Therefore there may also be no significant interaction with the clearance of other CYP3A4 substrates.
The solubility of erlotinib is pH dependent. pH increases decrease the solubility of erlotinib. Drugs that alter the pH of the upper GI tract may alter the solubility of erlotinib, which in turn may affect its bioavailability. The AUC and Cmax of erlotinib were reduced by 46% and 61%, respectively, when erlotinib was combined with the proton pump inhibitor omeprazole. there was no change in Tmax or half-life. When erlotinib was combined with ranitidine, a 300 mg H2 receptor blocker, the AUC and Cmax of erlotinib were reduced by 33% and 54%, respectively. Therefore, when possible, erlotinib should be avoided in combination with drugs that reduce gastric acid production. Increasing the dose of erlotinib in combination with these drugs is unlikely to compensate for the reduction in exposure. However, the AUC and Cmax of erlotinib were reduced by only 15% and 17%, respectively, when erlotinib was administered spaced with ranitidine (ranitidine 150 mg twice daily, 2 hours before or 10 hours after administration of erlotinib). H2 receptor blocking agents such as ranitidine should be considered and spaced for administration if the patient needs to be treated with such drugs. Erlotinib must be given 2 hours before or 10 hours after the administration of an H2-blocking agent.
Erlotinib is a substrate of the P-glycoprotein active substrate transporter and its combination with Pgp inhibitors (e.g., cyclosporine and verapamil) may alter the distribution and/or elimination of erlotinib. The effect of the interaction outcome on toxicity (e.g., CNS) is not known and should be used with caution in this setting.
Erlotinib increases platinum concentrations. In one clinical study, the combination of erlotinib with carboplatin and paclitaxel increased total platinum AUC0-48 by 10.6%. Although the difference was statistically significant, the magnitude of the difference was not considered clinically relevant. In clinical practice, there may be some other common factors that contribute to increased carboplatin exposure, such as renal injury. Carboplatin and paclitaxel had no significant effect on the pharmacokinetics of erlotinib.
Capecitabine may increase the concentration of erlotinib. Erlotinib showed a statistically significant increase in AUC and a critically significant increase in Cmax values when combined with capecitabine compared with data from another erlotinib monotherapy study. Erlotinib had no significant effect on the pharmacokinetics of capecitabine.
The combination of this product with statins may increase the incidence of statin-induced myopathy including the rare form of rhabdomyolysis.
Smoking is known to induce CYP1A1 and CYP1A2, resulting in a 50-60% reduction in erlotinib exposure, and smokers are advised to quit (see [Dosage] and [Pharmacokinetics] Special Populations).
Drug Overdose]
A single oral dose of 1000 mg in healthy subjects and a single oral dose of 1600 mg per week in cancer patients can be tolerated. The twice-daily 200 mg dose was poorly tolerated in healthy subjects for only a few days. Based on information from these trials, unacceptable serious adverse reactions (e.g., diarrhea, rash, and elevated hepatic transaminases, see [DOSAGE AND ADMINISTRATION]) may occur at doses above the recommended dose of 150 mg per day. Erlotinib should be discontinued and symptomatic treatment given in case of suspected overdose.
Pharmacology and Toxicology
Pharmacological effects
Erlotinib is a tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor I (also known as HER1). Erlotinib effectively inhibits intracellular EGFR phosphorylation, which is normally expressed on the surface of normal and tumor cells. In non-clinical models, inhibition of EGFR phosphorylation can cause cell growth arrest and/or cell death. The binding of erlotinib to EGFR with exon 19 deletion or exon 21 (L858R) mutation is higher than that of the wild-type receptor. EGFR mutations can lead to structural activation of anti-apoptotic and proliferative signaling pathways, and the effective blockade of EGFR-mediated signaling pathways by erlotinib in EGFR-sensitive mutation-positive tumors is mainly due to the binding of erlotinib to the EGFR mutation kinase The effect of erlotinib in blocking the EGFR-mediated signaling pathway in EGFR-sensitive mutation-positive tumors is mainly caused by the tight binding of erlotinib to the ATP-binding site in the structural domain of EGFR mutation kinase. As the downstream signaling pathway is blocked, cell proliferation is arrested and cell death is induced via the intrinsic apoptotic pathway. Tumor regression was observed in a mouse model expressing the EGFR mutation.
Toxicological studies
Repeated administration toxicity tests showed corneal lesions (atrophy, ulceration), skin lesions (follicular degeneration, inflammation, reddening and hair loss), ovarian atrophy, liver tissue necrosis, renal papillary necrosis and renal tubular dilatation and gastrointestinal reactions (delayed gastric emptying and diarrhea) in at least one animal species. Red blood cell parameters decreased and white blood cell parameters (mainly neutrophils) increased. Dosing-related elevations in ALT, AST and bilirubin were observed. All of the above reactions occurred at levels well below clinical drug exposure.
Slight phototoxicity was seen with erlotinib under UV irradiation.
Genotoxicity
Results of the erlotinib Ames test, human lymphocyte chromosome aberration test, mammalian cell mutation test, and mouse bone marrow micronucleus test were negative.
Reproductive toxicity
Erlotinib did not impair fertility in male and female rats.
Administration of erlotinib during organogenesis in rabbits at plasma drug concentrations up to 3 times the plasma drug concentration at approximately the clinically recommended dose (AUC of 150 mg/d) caused maternal toxicity resulting in embryo/fetus death and abortion. Exposure of rabbits and rats administered during organogenesis at approximately the clinically recommended dose did not increase embryo/fetus mortality or abortion. Erlotinib at 30 mg/m2/d or 60 mg/m2/d (approximately 0.3 or 0.7 times the clinically recommended dose based on body surface area) administered to female rats from pre-mating to the first week of gestation caused early fetal resorption resulting in decreased viable litter size.
Erlotinib is considered to be potentially teratogenic based on its mechanism of action. No teratogenicity was observed in rabbits given up to 600 mg/m2/d of erlotinib (plasma drug concentration approximately 3 times the clinically recommended dose of 150 mg/d plasma drug concentration) and rats given up to 60 mg/m2/d of erlotinib (approximately 0.7 times the clinically recommended dose of 150 mg/d converted to body surface area) during organogenesis.
Carcinogenicity
In a two-year carcinogenicity test in mice and rats, erlotinib was given orally up to 60 mg/kg/d in mice (exposure approximately 10 times the clinically recommended dose of 150 mg/d); up to 10 mg/kg/d in male rats (exposure approximately twice the clinically recommended dose of exposure), and up to 5 mg/kg/d in female rats (exposure slightly less than the clinically recommended dose of exposure). d (exposure slightly lower than the clinically recommended dose), and no carcinogenicity was observed.
Pharmacokinetics]
There is a lack of data on pharmacokinetic studies in Chinese. The following information is from overseas clinical studies.
Absorption and Distribution
The bioavailability of erlotinib is approximately 60% at the oral dose of 150 mg, with peak plasma concentrations reached 4 hours after dosing. Food significantly increases bioavailability to almost 100%. Approximately 93% of erlotinib is bound to albumin and alpha 1 acidic glycoprotein (AAG) after absorption. The apparent volume of distribution of erlotinib is 232 liters. In a study examining the distribution of erlotinib in human tumor tissue, four patients (three with NSCLC and one with laryngeal cancer) receiving erlotinib 150 mg orally once daily showed an average erlotinib concentration of 1,185 ng/g tissue in tumor tissue in surgically excised tumor samples on day 9 of treatment. This corresponds to an overall mean of 63% (5-161%) of the steady-state peak concentration. The mean concentration of the major active metabolite in tumor tissue was 160 ng/g tissue, which corresponds to 113% (88-130%) of the overall mean of steady-state peak plasma concentrations. Plasma protein binding was nearly 95%. Erlotinib binds to serum creatinine and alpha-1 acidic glycoprotein (AAG).
Metabolism and Clearance
In vitro cytochrome P450 analysis indicates that erlotinib is metabolized primarily by CYP3A4 and to a lesser extent by CYP1A2 and the extrahepatic isoenzyme CYP1A1. Extrahepatic metabolism includes CYP3A4 metabolism in the small intestine, CYP1A1 metabolism in the lung, and 1B1 metabolism in tumor tissue, which may have a role in the metabolic clearance of erlotinib.
Three metabolic pathways have been demonstrated: 1) O-demethylation of single or double side chains, followed by further oxidation to carboxylic acids; 2) oxidation of the acetylenic group, followed by further hydrolysis to aromatic carboxylic acids; and 3) hydroxylation of the aromatic ring of the phenylethynyl group. The O-demethylation of either of the two side chains of erlotinib yields the major metabolites OSI-420 and OSI-413, which were shown to be comparable in potency to erlotinib in non-clinical in vitro assays and in vivo tumor models, with plasma levels <10 % of erlotinib, but with a pharmacokinetic profile similar to that of erlotinib.
After oral administration of a 100 mg dose, 91 % of the drug was recovered, including 83 % in feces (prodrug at 1 % of the given dose) and 8 % in urine (prodrug at 0.3 % of the given dose).
Pharmacokinetic analysis of the population of 591 patients taking a single dose of erlotinib showed a median half-life of 36.2 hours. Therefore it took 7-8 days to reach steady-state plasma concentrations. There was no significant correlation between clearance and age. Clearance of erlotinib was increased by 24% in smokers.
A complementary population pharmacokinetic study was conducted in 291 patients with NSCLC in which erlotinib monotherapy was used for maintenance therapy. The analysis showed that the covariates affecting erlotinib clearance in this patient population were similar to the results of the previous single-agent pharmacokinetic analysis, and no new covariate effects were identified.
Results of a separate pharmacokinetic analysis of 204 pancreatic cancer patients receiving the erlotinib + gemcitabine combination showed that the factors affecting erlotinib clearance in the pancreatic cancer trial were similar to previous single-agent pharmacokinetic analyses. No new influencing factors were observed. Co-administration with gemcitabine had no effect on the plasma clearance of erlotinib.
Special Populations
Population pharmacokinetic analysis showed no clinically meaningful relationship between predicted apparent clearance and patient age, weight, gender and race. Patient factors associated with erlotinib pharmacokinetics were total serum bilirubin, AAG, and current smoking status. Increases in total serum bilirubin concentration and AAG concentration were associated with decreases in erlotinib clearance, and the clinical relevance of these differences is not known.
Pediatric and elderly patients have not been studied specifically.
Patients with abnormal liver function
Erlotinib is primarily cleared in the liver. Patients with moderate hepatic impairment (Child-Pugh classification 7-9) have similar erlotinib exposure to patients with normal liver function, including patients with primary hepatocellular carcinoma and liver metastases. In patients with solid tumors with moderate hepatic insufficiency (Child-Pugh classification 7-9), the geometric means of erlotinib AUC 0-t and Cmax were 27,000 ng-h/mL and 805 ng/mL, respectively, compared with values in patients with severe hepatic insufficiency (including patients with primary hepatocellular carcinoma or hepatic metastases), which were were 29300 ng-h/mL and 1090 ng/mL. Although the Cmax was lower in patients with moderate hepatic impairment and the difference was statistically significant, the difference was not considered clinically significant. No data are available regarding the effect of severe hepatic impairment on erlotinib pharmacokinetics. In a population pharmacokinetic analysis, an increase in total bilirubin serum concentrations was found to be associated with a slower rate of erlotinib clearance.
Patients with abnormal renal function
Less than 9% was secreted in the urine after single dose administration. No clinical trials were conducted in patients with abnormal renal function.
Patients who smoke
Pharmacokinetic studies in non-smoking and currently smoking healthy volunteers have shown that smoking leads to increased erlotinib clearance and decreased exposure. This was confirmed by an oral erlotinib 150 mg daily pharmacokinetic study in non-smoking and currently smoking healthy volunteers. The geometric mean Cmax was 1056 ng/mL in nonsmokers and 689 ng/mL in smokers, with a mean smoker to nonsmoker ratio of 65.2% (95% CI: 44.3-95.9, p=0.031). The geometric mean AUC0-inf was 18726 ng-h/mL for nonsmokers and 6718 ng-h/mL for smokers, with a mean smoker to nonsmoker ratio of 35.9% (95% CI: 23.7-54.3, p<0.0001). The C24h geometric mean was 288 ng/mL for nonsmokers and 34.8 ng/mL for smokers, with a mean ratio of 12.1% (95% CI: 4.82-30.2, p=0.0001) for smokers to nonsmokers (16 subjects each in the smoking and never-smoking/previous smoking groups). The reduction in exposure in current smokers may be due to induction of pulmonary CYP1A1 and hepatic CYP1A2.
In the pivotal phase III NSCLC clinical trial (BR.21), steady-state plasma trough concentrations of erlotinib in current smokers were 0.65 µg/mL (n=16), approximately 1/2 that of previous or never smokers (1.28 µg/mL, n=108), with a 24% increase in apparent plasma clearance of erlotinib.
In the phase I dose creep study in patients with NSCLC who were smoking, steady-state pharmacokinetic analysis showed a proportional increase in erlotinib exposure with dose as erlotinib was increased from 150 mg to the maximum tolerated dose of 300 mg. At the 300 mg dose level, the steady-state plasma trough concentration in patients who were smoking was 1.22 µg/mL (n=17) (see [Dosage] and [ Drug Interactions]).
Interactions
Erlotinib is primarily metabolized by CYP3A4, so presumably inhibitors of CYP3A4 would increase its exposure. The AUC of erlotinib was increased by 2/3 when combined with ketoconazole, a strong inhibitor of CYP3A4 (see [Drug Interactions], [Dosage] in the Dose Adjustment section).
Pre-treatment use or concomitant use of the CYP3A4 inducer rifampin resulted in a 3-fold increase in erlotinib clearance and a 2/3 decrease in erlotinib AUC (see [Drug Interactions] and [Dosage] in the Dosage Adjustment section).
In a Phase Ib clinical trial, no significant interaction occurred between the pharmacokinetics of gemcitabine and erlotinib.
Population pharmacokinetic analysis showed that opioids increased erlotinib exposure by approximately 11%.
Storage】Seal and store at room temperature.
Package】 Aluminum-plastic package, 7 tablets/plate, 2 plates/box.
Expiration date】 12 months
Execution Standard
Approval number
Manufacturer
Company Name: Shanghai Chuangnuo Pharmaceutical Co.
Address: No. 9125 Huinan Highway, Huinan Town, Pudong New Area, Shanghai
Postcode：201300
Telephone number: 86-21-51323308
Fax Number: 86-21-58003453
E-mail address: [email protected]
Web address: www.acebright.com.cn