Erlotinib Hydrochloride Tablets

Mechanism of Action The clinical anti-tumor mechanism of erlotinib has not been fully clarified. Erlotinib can inhibit the phosphorylation of intracellular tyrosine kinases associated with epidermal growth factor receptor (EGFR). Whether it has specific inhibitory effects on other tyrosine kinase receptors has not been fully clarified. EGFR is expressed on the surface of normal cells and tumor cells. No evidence of potential carcinogenicity was observed in preclinical studies. In genotoxicity studies, erlotinib was neither genotoxic nor teratogenic. Long-term carcinogenicity studies have been started in rats and mice, and no precancerous proliferative lesions have been observed in 6-month chronic toxicity studies. The genotoxicity of erlotinib was analyzed in a series of in vitro experiments (bacterial mutation, human lymphocyte chromosome aberration and mammalian cell mutation) and in vivo mouse bone marrow micronucleus experiments, and no genotoxicity was found. Erlotinib does not affect the fertility of female and male rats. Maternal toxicity can occur when the plasma drug concentration of erlotinib in rabbits reaches approximately 3 times the plasma concentration of humans (AUC of 150 mg per day), leading to embryo/fetal death and abortion. Administration during organogenesis did not increase embryonic/fetal death and abortion in rabbits and rats when plasma drug concentrations reached approximately human plasma concentrations (based on AUC). However, female rats receiving 30 mg/㎡/d to 60 mg/㎡/d of erlotinib (equivalent to 0.3 to 0.7 times the clinical dose calculated based on mg/㎡) before mating to the first week of pregnancy can cause early absorption and lead to a decrease in the number of viable fetuses. No teratogenic effects were observed in rabbits and rats.

The main ingredient of this product is erlotinib hydrochloride. Chemical name: N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinolamine hydrochloride.

Tablets: Round, biconvex, white coated tablets printed with the Tarceva, 150 and Tarceva logo in brown on one side and blank on the other side.

Erlotinib can be tried as a third-line treatment for locally advanced or metastatic non-small cell lung cancer that has failed two or more chemotherapy regimens. This indication is based on the results of a foreign Phase III clinical study mentioned above. The efficacy of second-line treatment for non-small cell lung cancer in Chinese people needs to be confirmed by further clinical studies. In two multicenter placebo-controlled, randomized Phase III trials for the first-line treatment of patients with locally advanced or metastatic NSCLC, the results showed that there was no clinical benefit from taking erlotinib simultaneously with platinum-based chemotherapy (carboplatin-paclitaxel; or gemcitabine-cisplatin), so it is not recommended for first-line treatment in the above situation.

Pregnancy Category D Adequate, controlled studies of erlotinib have not been conducted in pregnant women. Animal studies have shown some reproductive toxicity. The potential risk to humans is unknown. Women of childbearing age should avoid becoming pregnant while taking erlotinib. Adequate contraception should be used during treatment and for at least 2 weeks after completion of treatment. Treatment should be continued in pregnant women 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 informed of the potential risk to the fetus and the possibility of causing miscarriage. It is unknown whether erlotinib is secreted in human milk. Because many drugs are secreted in human milk and the effects of erlotinib on the infant have not been studied, advise women to avoid breastfeeding while taking erlotinib.

Safety data are from 856 cancer patients treated with erlotinib monotherapy abroad, 308 patients receiving erlotinib 100 or 150 mg combined with gemcitabine for pancreatic cancer, and 1228 patients treated with erlotinib and chemotherapy simultaneously. Serious adverse events, including fatal events, have been reported in patients taking erlotinib for NSCLC, pancreatic cancer, and other advanced solid tumors (see [Precautions] Warning-Pulmonary Toxicity and [Dosage and Administration] Dose Adjustment). A randomized, double-blind, placebo-controlled trial BR.21 was conducted in 731 patients with locally advanced or metastatic NSCLC in 17 countries who had failed at least one chemotherapy regimen. Patients were randomized in a 2:1 ratio to receive erlotinib 150 mg or placebo once daily until disease progression or unacceptable toxicity. Regardless of the cause, the most common adverse reactions were rash (75%) and diarrhea (54%). Most of them were grade 1 or 2 and could be treated without interrupting medication. The incidence of grade 3/4 rash and diarrhea in patients treated with erlotinib was 9% and 6%, respectively. The proportion of patients treated with erlotinib who discontinued the trial due to rash or diarrhea was 1%. 6% and 1% of patients required dose reduction due to rash and diarrhea, respectively. The median time to onset of rash in BR.21 was 8 days, and the median time to onset of diarrhea was 12 days. In BR.21, at least 10% of patients in the erlotinib treatment group experienced adverse events, which was higher than the placebo group (ge; 3%). The NCI-CTC grading summary is shown in Table 1. Listed in the table are adverse reactions assessed by the sponsor as related to erlotinib treatment. Table 1: Adverse events with a higher incidence in the erlotinib group than in the placebo group (ge; 3%) and an incidence of ge; 10% in the BR.21 study Erlotinib N = 485 Placebo N = 242 NCI-CTC grade Any grade 3 Grade 4 Any grade 3 Grade 4 Adverse drug reaction Noun %%%%%%% Total patients with AE 9940 2296 3622 Infections and infestations Infections* 2440 1520 Metabolic and nutritional disorders Decreased appetite 528 138 51 Eye diseases Conjunctivitis 1210 210 Keratoconjunctivitis sicca 1200 300 Respiratory tract, Chest and mediastinal abnormalitiesDyspnea411711351511Cough33402920Gastrointestinal abnormalitiesDiarrhea54611810Nausea33302420Vomiting23211920Stomatitis1710300Abdominal pain1121711Skin and subcutaneous tissue abnormalitiesRash75811700Itch1310500Dry skin1200400General malaise and medication site conditionsFatigue5214445164*Severe infections with or without neutropenia, including pneumonia, sepsis, and cellulitis. Abnormal liver function tests (including elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin) may be observed in NSCLC patients treated with erlotinib 150 mg monotherapy. The elevations were mainly transient or related to liver metastases. Grade 2 ALT elevation (2.5 to 5.0 times the upper limit of normal) occurred in 4% and 1% of patients treated with erlotinib and placebo, respectively. Grade 3 ALT elevation (5.0 to 20.0 times the upper limit of normal) did not occur in patients treated with erlotinib. Dose reduction or suspension of treatment should be considered when liver function is severely abnormal (see [Dosage and Administration] Dose Adjustment). Pancreatic cancer The most common adverse reactions in pancreatic cancer patients treated with 100 mg erlotinib gemcitabine were fatigue, 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 onset time of 10 days and 15 days, respectively, each leading to a reduction in treatment in 2% of patients and no more than 1% of patients discontinuing the drug. The incidence of some specific adverse reactions in the 150 mg group (23 cases), including rash, was higher, resulting in more frequent dose reductions or discontinuations. In the key study PA.3, at least 10% of patients in the 100 mg erlotinib gemcitabine group experienced adverse events, and the incidence of adverse reactions was higher than that in the placebo gemcitabine group (ge; 3%). The NCI-CTC classification of adverse events is summarized in Table 2. Listed in the table are adverse reactions assessed by the sponsor as being related to erlotinib treatment. Table 2: Adverse events with an incidence of ge>10% in the 100 mg erlotinib gemcitabine group and an incidence higher than that in the placebo gemcitabine group (ge>3%) in the PA.3 study Erlotinib gemcitabine 1000 mg/㎡ IV, N=259 Placebo gemcitabine 1000 mg/㎡ IV, N=256 NCI-CTC grade Any Grade 3 Grade 4 Any Grade 3 Grade 4 Adverse drug reaction Noun %%%%%% Fatigue 731 4270 132 Rash 6950 3010 Nausea 6070 5870 Decreased appetite 5261 5251 Diarrhea 4851 3620 Abdominal pain 4691 45121 Vomiting 4271 4141 Weight loss 3920 2910 Infection* 391333092 Edema37313621 Fever36303040 Constipation31313451 Bone pain25412320 Dyspnea24512350 Oral mucositis22101200 Myalgia21102010 Depression19201410 Dyspepsia17101310 Cough16001100 Vertigo15101301 Headache15101000 Insomnia15101610 Alopecia14001100 Anxiety13101110 Neuropathy13111010 Flatulence1300910 Chills1200900* Severe infections, with or without neutropenia, including pneumonia, sepsis, and cellulitis. In the pancreatic cancer clinical trial, deep vein thrombosis occurred in 10 patients in the erlotinib/gemcitabine group (incidence 3.9%). In contrast, deep vein thrombosis occurred in 3 patients in the placebo/gemcitabine group (incidence 1.2%). The overall incidence of grade 3 or 4 thrombotic events, including deep vein thrombosis, was similar in both treatment groups: 11% in the erlotinib-gemcitabine group and 9% in the placebo-gemcitabine group. No difference was observed in grade 3 or 4 hematologic laboratory toxicity between the erlotinib-gemcitabine group and the placebo-gemcitabine group. Serious adverse events (ge; NCI-CTC grade 3) with an incidence of less than 5% in the erlotinib-gemcitabine group included syncope, arrhythmia, intestinal obstruction, pancreatitis, hemolytic anemia including microangiopathic hemolytic anemia due to thrombocytopenia, myocardial infarction/ischemia, cerebrovascular accident including cerebral hemorrhage, and renal insufficiency (see [Precautions] Warnings). Abnormal liver function tests (including elevated ALT, AST, and bilirubin) were observed in pancreatic cancer patients treated with erlotinib gemcitabine. The most severe NCI-CTC grade of liver function abnormalities that occurred are listed in Table 3. If the changes in liver function are severe, the dose reduction or discontinuation of erlotinib should be considered (see [Dosage and Administration] Dose Adjustment section). Table 3: Abnormal liver function tests in patients treated for pancreatic cancer (most severe NCI-CTC grade): 100 mg group Erlotinib Gemcitabine 1000 mg/m2 IV, N=259 Placebo Gemcitabine 1000 mg/m2 IV, N=256 NCI-CTC grade Grade 2 Grade 3 Grade 4 Grade 2 Grade 3 Grade 4 Bilirubin 17% 10% 1% 11% 10% 3% ALT 31% 13% 1% 22% 9% 0% AST 24% 10% 1% 19% 9% 0% Other observational data (based on all clinical study data) Safety data were from more than 800 patients who received at least one dose of 150 mg erlotinib monotherapy and more than 300 patients who received erlotinib 100 or 150 mg in combination with gemcitabine. The following adverse reactions were observed in patients treated with erlotinib 150 mg monotherapy or erlotinib 100 mg or 150 mg in combination with gemcitabine. The following terms are used to rank the incidence of adverse reactions: very common (ge; 1/10); common (ge; 1/100, 1/10); uncommon (ge; 1/1,000, 1/100); rare (ge; 1/10,000, 1/1000); very rare (1/10,000), including single reports. Very common adverse reactions are shown in Tables 1 and 2, and the frequency of other adverse reactions is summarized below. Gastrointestinal disorders: Common gastrointestinal bleeding has been reported in NSCLC trials and combination trials in pancreatic cancer, some of which are related to concomitant use of warfarin or nonsteroidal anti-inflammatory drugs (see [Precautions] Increased International Normalized Ratio and Potential for Bleeding). These reports include bleeding from peptic ulcers (gastritis, gastric and duodenal ulcers), hemoptysis, blood in the stool, melena, and possible bleeding from colitis (see [Precautions]). Abnormal liver function tests: Abnormal liver function tests (including elevated ALT, AST, and bilirubin) were frequently observed in clinical trials of erlotinib, especially in the PA3 study. Most were mild to moderate, transient, or related to liver metastases. Rare cases of liver failure (including death) have been reported during the use of erlotinib. Confounding factors include preexisting liver disease or concomitant use of hepatotoxic drugs. Eye diseases: Keratitis occurred frequently in clinical trials of erlotinib. Conjunctivitis occurred frequently in trials of pancreatic cancer. Corneal ulcers are very rare and are a complication of mucosal inflammation in patients treated with erlotinib. Respiratory, chest, and mediastinal abnormalities: Serious interstitial lung disease (ILD)-like events, including death, have been reported in patients treated with erlotinib for NSCLC and other progressive solid tumors (see Precautions). Epistaxis was reported in both NSCLC and pancreatic cancer trials. Skin and subcutaneous tissue abnormalities: Dry skin was common in pancreatic cancer trials. Alopecia was common in NSCLC trials. Overall, the safety of erlotinib, whether used as a single agent or in combination with gemcitabine, did not differ significantly between women and men, between young people and those over 65 years old, or between Caucasian and Asian patients (see [Precautions] and [Use in the Elderly]).

It is contraindicated for those who are allergic to this product or its ingredients.

Precautions for children: The efficacy and safety of erlotinib have not been studied in children. Erlotinib is not recommended for use in children. Precautions for pregnancy and lactation: 1. Pregnancy category D 2. No adequate, controlled studies of erlotinib have been conducted in pregnant women. During the organogenesis period, when the plasma drug concentration of erlotinib in rabbits reached 3 times the human plasma concentration when 150 mg was administered daily, maternal toxicity occurred, leading to embryonic death and abortion. Female rats receiving erlotinib at a dose equivalent to 0.3 or 0.7 times the clinical dose of 150 mg (calculated based on mg/m2) before mating to the first week of pregnancy can cause early absorption and lead to a decrease in the number of viable fetuses. The potential risk to humans is unknown. Women of childbearing age 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 can only continue treatment if it is believed that the benefit to the mother outweighs the risk to the fetus. If erlotinib is used during pregnancy, patients should be aware of the potential harm to the fetus and the possibility of abortion. 3. It is unclear whether erlotinib is secreted in human milk. Because many drugs can be secreted into human milk and the effects of erlotinib on infants have not been studied, women are advised to avoid breastfeeding when using erlotinib. Elderly precautions: 1. NSCLC maintenance therapy Among all patients participating in randomized NSCLC maintenance therapy trials, approximately 66% of patients were younger than 65 years old, and 34% of patients were equal to or older than 65 years old. The hazard ratio for overall survival in patients under 65 years old was 0.78 (95% CI: 0.65, 0.95), and the hazard ratio for overall survival in patients 65 years old or older was 0.88 (95% CI: 0.68, 1.15). 2. Second/third-line treatment for NSCLC Among the total population participating in randomized NSCLC trials, 62% of patients were younger than 65 years old, while 38% were older than 65 years old. Survival benefits were obtained in both age groups (see [Clinical Trials]). 3. First-line treatment for pancreatic cancer In pancreatic cancer trials, 53% of patients were younger than 65 years old, while 47% were older than 65 years old. No meaningful safety and pharmacokinetic differences were observed between younger or older patients. Therefore, no dose adjustment is recommended for elderly patients.

Erlotinib is metabolized by the liver, mainly through CYP3A4, and to a lesser extent through CYP1A2 and the pulmonary isoenzyme CYP1A1. Any agent that metabolizes through these enzymes or an inhibitor or inducer of the enzyme may interact with erlotinib. Strong CYP3A4 inhibitors can reduce erlotinib metabolism and increase its plasma concentration. Compared with erlotinib alone, ketoconazole (200 mg twice a day for 5 days) leads to increased erlotinib exposure (mean erlotinib exposure increased by 86% [AUC]) and Cmax increased by 69% by inhibiting CYP3A4 metabolic activity. When erlotinib is combined with the CYP3A4 and CYP1A2 inhibitor ciprofloxacin, the exposure [AUC] and Cmax of erlotinib are increased by 39% and 17%, respectively. Therefore, care should be taken when erlotinib is combined with strong CYP3A4 inhibitors or CYP3A4/CYP1A2 inhibitors, and the erlotinib dose should be reduced if toxic effects are found. Strong CYP3A4 inducers can increase the metabolism of erlotinib and significantly reduce the blood concentration of erlotinib. Compared with erlotinib alone, rifampicin (600 mg once a day for 7 days) after administration of 150 mg erlotinib caused a 69% decrease in the average AUC of erlotinib by inducing CYP3A4 metabolic activity. If rifampicin has been used before treatment or during treatment, the average exposure [AUC] of erlotinib after a single dose of 450 mg is 57.5% of that after a single dose of 150 mg erlotinib without rifampicin treatment. If possible, other drugs that are not strong CYP3A4 inducible should be selected for treatment. For patients who need to be treated with strong CYP3A4 inducers of erlotinib (such as rifampicin), the dose should be considered to be increased to 300 mg under close monitoring of drug safety. If it can be well tolerated for more than 2 weeks, the dose can be further increased to 450 mg, while closely monitoring drug safety. Higher doses have not been studied under this condition. Pretreatment or co-administration of erlotinib had no effect on the clearance of the prototypic CYP3A4 substrates midazolam and erythromycin. Therefore, significant interactions with the clearance of other CYP3A4 substrates are unlikely to occur. Midazolam oral availability appears to be reduced by 24%, but this is not due to an effect on CYP3A4 activity. The solubility of erlotinib is pH-dependent. When pH increases, the solubility of erlotinib decreases. When erlotinib is co-administered with the proton pump inhibitor omeprazole, erlotinib exposure [AUC] and maximum concentration [Cmax] were reduced by 46% and 61%, respectively. There was no change in Tmax or half-life. Therefore, drugs that affect upper gastrointestinal pH may alter the solubility of erlotinib and, therefore, its bioavailability. Increasing the dose of erlotinib when used with these drugs is unlikely to compensate for the reduction in exposure. Smoking may reduce the plasma concentration of erlotinib, and smokers are advised to quit smoking (see [Pharmacokinetics]).

Store at 25℃. 15～30℃ is also acceptable. Keep the medicine out of reach of children. Valid for 36 months.

36 months