Erlotero

Erlotinib (Tarceva) instructions

Common name: Erlotinib

Trade name: Tarceva

Full names: Erlotinib, Tarceva, Erlotinib hydrochloride tablets, Erlotinib, Tarce va,Erlonat

Indications of Erlotinib

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 the aforementioned phase III clinical study abroad.

The efficacy of second-line treatment for Chinese non-small cell lung cancer needs to be confirmed by further clinical studies.

Two multicenter placebo-controlled randomized phase III trials for the first-line treatment of patients with locally advanced or metastatic NSCLC showed that erlotinib had no clinical benefit when combined with platinum-based chemotherapy (carboplatin + paclitaxel; or gemcitabine + cisplatin), and therefore is not recommended for first-line treatment in the above conditions.

Usage and Dosage of Erlotinib

This product must be used under the guidance of a doctor with experience in using this type of drug, and can only be used in the National Clinical Trial Pharmacology Base or tertiary A-level hospitals.

The recommended dose of erlotinib alone for non-small cell lung cancer is 150 mg/day, taken at least 1 hour before or 2 hours after eating. Continue treatment until disease progression or intolerable toxicity occurs. There is no evidence that patients benefit from continuing treatment after progression.

Erlotinib dose adjustment

In patients who develop new acute exacerbations or progressive pulmonary symptoms, such as dyspnea, cough, and fever, erlotinib treatment should be suspended for diagnostic evaluation. If ILD (interstitial lung disease) is confirmed, erlotinib should be discontinued and appropriate treatment administered (see Precautions and Warnings - Pulmonary Toxicity).

Diarrhea can usually be controlled with loperamide. Patients with severe diarrhea who are refractory to loperamide or who become dehydrated require dose reduction and temporary discontinuation of treatment. Patients with severe skin reactions may also require dose reduction and temporary discontinuation of treatment.

If dose reduction is necessary, erlotinib should be reduced by 50 mg each time.

Dose reduction should be considered when using drugs with strong CYP3A4 inhibitors such as atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, ditroleandomycin (TAO) and voriconazole, otherwise serious adverse events may occur.

Using the CYP3A4 inducer rifampicin before treatment can reduce the AUC of erlotinib by 2/3. Alternative treatments without CYP3A4-inducing activity should be considered. If alternative treatments are not available, doses of erlotinib higher than 150 mg should be considered. If the dose of erlotinib is increased, the dose should be reduced when rifampicin or other inducers are discontinued. Other CYP3A4 inducers include, but are not limited to, rifabutin, rifapentine, phenytoin, carbamazepine, phenobarbital, and St. John's wort, and the use of these drugs should also be avoided if possible (see Precautions and Drug Interactions).

Erlotinib is eliminated by hepatic metabolism and biliary secretion. Erlotinib should therefore be used with caution in patients with liver dysfunction. If serious adverse reactions occur, a dose reduction or suspension of erlotinib should be considered (see Pharmacokinetics - Special Populations - Patients with Abnormal Hepatic Function, Precautions - Patients with Abnormal Hepatic Function and Adverse Reactions).

Erlotinib adverse reactions

Safety data come from 856 foreign cancer patients treated with erlotinib monotherapy, 308 patients receiving erlotinib 100 or 150 mg combined with gemcitabine for the treatment of pancreatic cancer, and 1,228 patients treated with erlotinib and chemotherapy simultaneously.

Serious adverse events, including fatal events, have been reported in patients taking erlotinib for the treatment of NSCLC, pancreatic cancer, and other advanced solid tumors (see Precautions - Warnings - Pulmonary Toxicity and Dosage and Administration - Dose Adjustments).

Non-small cell lung cancer (NSCLC)

A randomized, double-blind, placebo-controlled trial BR.21 was conducted in 731 patients from 17 countries with locally advanced or metastatic NSCLC who had failed at least one previous chemotherapy regimen. Patients were randomized in a 2:1 ratio to receive erlotinib 150 mg once daily or placebo until disease progression or unacceptable toxicity.

The most common adverse reactions regardless of cause were rash (75%) and diarrhea (54%). Most of them are 1st or 2nd degree, which can be dealt with without interrupting medication. The incidence of grade 3/4 rash and diarrhea in erlotinib-treated patients was 9% and 6%, respectively. The proportion of erlotinib-treated patients 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 that in the placebo group (≥3%).

Liver function test abnormalities (including elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin) were observed in NSCLC patients treated with erlotinib 150 mg monotherapy. The increase is mainly transient or related to liver metastasis. Grade 2 ALT elevations (>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 elevations (>5.0 to 20.0 times the upper limit of normal) did not occur in patients treated with erlotinib. When liver function abnormalities are severe, dose reduction or treatment suspension should be considered (see Dosage and Administration - Dose Adjustment).

Pancreatic cancer

The most common adverse reactions in patients with pancreatic cancer who received 100 mg of 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 was 5% in treated patients, with a median incidence of 10 days and 15 days, respectively, resulting in 2% of patients requiring dose reduction and no more than 1% of patients discontinuing treatment.

Some adverse reactions specific to the 150 mg group (23 cases) included a higher incidence of rash, resulting in more frequent dose reductions or drug discontinuations.

In the key study PA.3, at least 10% of patients in the 100 mg erlotinib + gemcitabine treatment group experienced adverse events, and the incidence of adverse reactions was higher than that in the placebo + gemcitabine group (≥3%).

In a pancreatic cancer clinical trial, 10 patients in the erlotinib/gemcitabine group developed deep vein thrombosis (incidence 3.9%). In contrast, three patients in the placebo/gemcitabine group developed deep vein thrombosis (incidence 1.2%). The overall incidence of grade 3 or 4 thrombotic events, including deep vein thrombosis, was similar in the two treatment groups: 11% in the erlotinib + gemcitabine group and 9% in the placebo + gemcitabine group.

There were no differences in grade 3 or 4 hematology laboratory toxicities between the erlotinib + gemcitabine group and the placebo + gemcitabine group.

Serious adverse events (≥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 Precautions - Warnings).

Liver function test abnormalities (including elevated ALT, AST, and bilirubin) were observed in patients with pancreatic cancer treated with erlotinib + gemcitabine. If changes in liver function are severe, consideration should be given to reducing the dosage of erlotinib or discontinuing the drug (see Dosage and Dosage - Dose Adjustment section).

Gastrointestinal abnormalities:

Common gastrointestinal bleeding has been reported in NSCLC trials and combination trials in pancreatic cancer, some related to concomitant use of warfarin or nonsteroidal anti-inflammatory drugs (see [Precautions] Increased International Normalized Ratio and Possibility of Bleeding section). These reports include bleeding from peptic ulcers (gastritis, gastric and duodenal ulcers), hemoptysis, hematochezia, melena, and possible bleeding from colitis (see Precautions).

Abnormal liver function:

Abnormal liver function tests (including elevated ALT, AST, and bilirubin) were frequently observed in clinical trials of erlotinib, especially in PA3 studies. Most are mild to moderate, transient or related to liver metastasis. Rare cases of liver failure, including death, have been reported during use of erlotinib. Confounding factors include preexisting liver disease or concomitant use of hepatotoxic drugs.

Eye disorders:

Keratitis occurred frequently during clinical trials of erlotinib. Conjunctivitis occurs frequently in pancreatic cancer trials.

Corneal ulcers are very rare and are complications of mucosal inflammation in patients receiving erlotinib.

Respiratory, thoracic, and mediastinal abnormalities:

Severe interstitial lung disease (ILD)-like events, including death, have been reported in patients treated with erlotinib in NSCLC and other progressive solid tumors (see Precautions).

Epistaxis has been reported in trials of NSCLC and pancreatic cancer.

Skin and subcutaneous tissue abnormalities:

Dry skin is commonly seen in trials for pancreatic cancer. Hair loss is common in trials of NSCLC.

Overall, the safety profile of erlotinib, whether used as monotherapy or in combination with gemcitabine, did not differ significantly between women and men, between younger adults and those over 65 years of age, or between Caucasian and Asian patients (see Precautions and Use in the Elderly).

Tarceva Contraindications

Contraindicated for those allergic to this product and its ingredients.

Tarceva Precautions

This product must be used under the guidance of doctors with experience in the use of such drugs, and can only be used in the national tumor drug clinical trial base or tertiary A hospitals.

Erlotinib may have clinically significant drug interactions.

Warnings

Pulmonary Toxicity

Severe interstitial lung disease-like events, including fatal cases, have occasionally been reported in patients receiving erlotinib for NSCLC, pancreatic cancer, or other solid tumors. In the randomized monotherapy NSCLC trial (see Clinical Trials), the incidence of interstitial lung disease-like events (0.8%) was the same in the erlotinib and placebo groups. In trials of pancreatic cancer 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.

Across all trials (including trials without control groups and trials with concurrent chemotherapy), a total of 4900 patients treated with erlotinib, the overall incidence rate was approximately 0.6%. Diagnostic reports in patients with suspected ILD-like events include pneumonia, radiation pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, bronchiolitis obliterans, pulmonary fibrosis, acute respiratory distress syndrome, pulmonary infiltrates, and alveolaritis. Symptoms can appear from 5 days to more than 9 months (median 39 days) after taking erlotinib. Most cases are associated with other causes of interstitial lung disease, such as concurrent or previous chemotherapy, previous radiation therapy, preexisting interstitial lung disease, metastatic lung disease, or pulmonary infection.

In the event of new acute exacerbations or progressive unexplained pulmonary symptoms such as dyspnea, cough, and fever, erlotinib therapy should be temporarily discontinued during diagnostic evaluation. Once ILD (interstitial lung disease) is diagnosed, stop erlotinib treatment if necessary and give appropriate treatment (see Adverse Reactions and Dosage).

Diarrhea, dehydration, electrolyte imbalance, and renal failure

Patients receiving erlotinib may develop diarrhea, 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). Severe dehydration with hypokalemia and renal failure (including fatal) has occurred rarely, mainly in patients receiving concurrent chemotherapy. For patients who develop severe diarrhea or persistent diarrhea, or even dehydration, especially those with high risk factors (such as those who receive concurrent chemotherapy, have other symptoms or diseases, or have other basic factors including older age), erlotinib treatment should be interrupted, and appropriate measures should be taken to provide intravenous fluid rehydration to the patient. While replenishing fluids, monitor the patient's renal function and blood electrolytes, including serum potassium.

Myocardial infarction/myocardial ischemia

In pancreatic cancer clinical trials, 6 patients (incidence rate 2.3%) in the erlotinib/gemcitabine group developed myocardial infarction/myocardial ischemia, and 1 patient died due to myocardial infarction. In contrast, 3 patients in the placebo/gemcitabine group experienced myocardial infarction (incidence 1.2%), and 1 patient died due to myocardial infarction.

Cerebrovascular accidents

In clinical trials of pancreatic cancer, 6 patients (incidence rate 2.3%) in the erlotinib/gemcitabine group suffered cerebrovascular accidents, including one bleeding event, which was the only fatal event. In contrast, there were no cerebrovascular accidents in the placebo/gemcitabine group.

Microvascular hemolytic anemia caused by thrombocytopenia

In a pancreatic cancer clinical trial, 2 patients (incidence 0.8%) in the erlotinib/gemcitabine group developed microvascular hemolytic anemia caused by thrombocytopenia. Both patients were treated with erlotinib and gemcitabine simultaneously. In contrast, no microvascular hemolytic anemia due to thrombocytopenia occurred in the placebo/gemcitabine group.

Hepatitis, liver failure

Rare cases of liver failure, including death, have been reported during use of erlotinib. Confounding factors include preexisting liver disease or concomitant use of hepatotoxic drugs. Therefore, such patients should undergo regular liver function tests. Patients with severe liver function abnormalities should stop taking erlotinib (see Adverse Reactions).

Patients with abnormal liver function

Both in vitro and in vivo experiments have shown that erlotinib is mainly eliminated in the liver. Therefore, erlotinib exposure is increased in patients with abnormal hepatic function (see Pharmacokinetics: Special Populations—Patients with Abnormal Hepatic Function and Administration and Dosage Adjustments).

Elevated international normalized ratio and possible bleeding

In clinical trials, increased international normalized ratio (INR) and rare bleeding events, including gastrointestinal bleeding and non-gastrointestinal bleeding, have been reported in clinical trials, some related to the concurrent use of warfarin. Patients taking warfarin or other dicoumarol anticoagulants should have their prothrombin time or INR monitored regularly (see Adverse Reactions).

Usage in pregnant and lactating women

Pregnancy Category D

Adequate and controlled studies of erlotinib have not been conducted in pregnant women. Animal studies show some reproductive toxicity. Potential hazard to humans 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. Only pregnant women should continue treatment if it is believed that the benefits to the mother outweigh the harm to the fetus. If erlotinib is used during pregnancy, patients should be informed of the potential harm to the fetus and possible miscarriage.

It is unknown whether erlotinib is secreted in human breast milk. Because many drugs are excreted in human milk and the effects of erlotinib on infants have not been studied, it is recommended that women avoid breastfeeding while taking erlotinib.

Pediatric Use

The effectiveness and safety of erlotinib have not been studied in children.

Geriatric Medication

Among the total population participating in randomized trials of NSCLC, 62% of patients were younger than 65 years old, while 38% were over 65 years old. Survival benefit was seen in both age groups (see Clinical Trials). In the pancreatic cancer trial, 53% of patients were younger than 65 years old, while 47% were older than 65 years. No meaningful differences in safety and pharmacokinetics were seen between younger or older patients. Therefore, it is recommended that no dose adjustment is required in elderly patients.

Drug Interactions

Erlotinib is metabolized by the liver, mainly via CYP3A4, and to a lesser extent via CYP1A2 and pulmonary isoenzyme CYP1A1. Any agent metabolized by these enzymes or that is an inhibitor or inducer of the enzyme may interact with erlotinib.

Strong inhibitors of CYP3A4 can reduce the metabolism of erlotinib and increase its plasma concentration. Compared to erlotinib alone, ketoconazole (200 mg twice daily for 5 days) resulted in increased erlotinib exposure (mean 86% increase in erlotinib exposure [AUC]) and a 69% increase in Cmax by inhibiting CYP3A4 metabolic activity. When erlotinib was combined with the CYP3A4 and CYP1A2 inhibitor ciprofloxacin, the exposure [AUC] and Cmax of erlotinib increased by 39% and 17%, respectively. Therefore, care should be taken when combining erlotinib with strong inhibitors of CYP3A4 or with inhibitors of CYP3A4/CYP1A2. If toxic effects are found, the dose of erlotinib should be reduced.

Strong CYP3A4 inducers can increase the metabolism of erlotinib and significantly reduce the plasma concentration of erlotinib. Compared with erlotinib alone, administration of 150 mg of erlotinib followed by rifampicin (600 mg once daily for 7 days) resulted in a 69% reduction in the mean AUC of erlotinib through induction of CYP3A4 metabolic activity.

If rifampicin has been used before treatment or is concurrently used 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 of erlotinib without rifampicin treatment. If possible, alternative drug therapy that is not a strong inducer of CYP3A4 should be chosen. For patients who need to be treated with erlotinib + strong CYP3A4 inducers (such as rifampicin), the dose should be increased to 300 mg while closely monitoring drug safety. If the drug can be well tolerated for more than 2 weeks, the dose can be considered to be further increased to 450 mg while closely monitoring drug safety. Higher doses have not been studied under this condition.

Erlotinib pretreatment or coadministration had no effect on the clearance of the prototype CYP3A4 substrates midazolam and erythromycin. Therefore, significant interactions with the clearance of other CYP3A4 substrates are also unlikely to occur. The oral availability of midazolam appears to be reduced by 24%, but this is not due to an effect on CYP3A4 activity.

The solubility of erlotinib is related to pH value. As the pH increases, the solubility of erlotinib decreases. Coadministration of erlotinib with the proton pump inhibitor omeprazole reduced erlotinib exposure [AUC] and maximum concentration [Cmax] by 46% and 61%, respectively. There is no change in Tmax or half-life. Therefore, drugs that affect the pH of the upper gastrointestinal tract may alter the solubility of erlotinib and thereby alter its bioavailability. Increasing the dose of erlotinib when used with these drugs is unlikely to compensate for the decrease in exposure.

Smoking may reduce the plasma concentration of erlotinib, and smokers are advised to quit smoking (see Pharmacokinetics).

Overdose

A single oral dose of 1000 mg was tolerated in healthy subjects and in cancer patients a single oral dose of 1600 mg per week was tolerated. Doses of 200 mg twice daily were poorly tolerated by healthy subjects for only a few days. Based on the data from these trials, unacceptable serious adverse events (such as diarrhea, rash, and elevated hepatic transaminases, see Dosage and Administration) may occur when the recommended dose of 150 mg per day is exceeded. Erlotinib should be discontinued and symptomatic treatment should be instituted if overdose is suspected.

Tarceva clinical trials

The following information comes from foreign clinical studies.

Erlotinib monotherapy for non-small cell lung cancer

A randomized, double-blind, placebo-controlled trial was conducted to evaluate erlotinib monotherapy in patients with locally advanced or metastatic NSCLC who had failed at least one previous chemotherapy regimen. To evaluate the efficacy and safety of the treatment, 731 patients were randomized in a 2:1 ratio to receive once-daily erlotinib 150 mg or placebo (488 patients in the erlotinib group and 243 patients in the placebo group) until disease progression or unacceptable toxicity. The efficacy indicators of the trial include overall survival, objective response rate, and progression-free time (PFS). The duration of response is also evaluated. The main efficacy indicator is survival. The trial was conducted in 17 countries, and about 1/2 of the patients (326 cases) had EGFR expression data.

The relationship between the efficacy of erlotinib monotherapy in the treatment of NSCLC and the expression of EGFR protein (measured by immunohistochemistry)

The analysis of the relationship between EGFR expression and therapeutic effect is limited because only 326 (45%) patients had EGFR expression. EGFR expression was measured in patients who had tissue samples available before trial enrollment. Nonetheless, the survival of patients who tested EGFR expression and the efficacy of erlotinib monotherapy were almost completely consistent with the results in the overall trial population, suggesting that the EGFR testing population is a representative sample. Positive EGFR expression is defined as at least 10% of cells stained with EGFR, and the specific positive value in the EGFR pharmDxTM kit instructions is 1%. The pharmDx kit has not been validated for use in non-small cell lung cancer.

Erlotinib monotherapy can prolong the survival of patients in the EGFR-positive subgroup (N=185, HR=0.68, 95%CI=0.49-0.94) and prolong the survival of patients in the unmeasured EGFR subgroup (N=4 05, HR=0.77, 95%CI=0.61～0.98), but had no effect on the survival of patients in the EGFR negative subgroup (N=141, HR=0.93, 95%CI=0.63～1.36). However, the confidence intervals of EGFR-positive, negative and unmeasured subgroups are wide and overlap with each other, so it cannot be ruled out that erlotinib can also prolong survival in EGFR-negative NSCLC patients.

For the non-smoking subgroup of patients, EGFR status can also predict the survival benefit of erlotinib. Erlotinib has a more significant effect on prolonging survival in non-smoking and EGFR-positive patients (N=41, HR=0.28, 95%CI=0.13~0.61). There are too few non-smoking and EGFR-negative patients to draw conclusions.

The response rate of tumors in all EGFR subgroups: 11.3% in the EGFR-positive group, 9.5% in the EGFR-unmeasured group, and 3.8% in the EGFR-negative group. Progression-free survival was prolonged in the EGFR-positive subgroup (HR=0.49, 95%CI=0.35-0.68), also in the unmeasured EGFR subgroup (HR=0.60, 95%CI=0.47-0.75), and was uncertain in the EGFR-negative subgroup (HR=0.80, 95%CI=0.55-1.16).

Two multi-center placebo-controlled randomized trials of erlotinib combined with chemotherapy in the treatment of NSCLC included more than 1,000 patients for first-line treatment of locally advanced or metastatic NSCLC. The results showed that there was no clinical benefit from taking erlotinib concurrently with platinum-based chemotherapy (carboplatin + paclitaxel, erlotinib, N = 526; gemcitabine + cisplatin, erlotinib, N = 580).

Tarceva Pharmacology and Toxicology

Mechanism of Action

The clinical anti-tumor mechanism of erlotinib has not yet been fully understood. Erlotinib inhibits 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 yet been fully clarified. EGFR is expressed on the surface of normal cells and tumor cells.

No evidence of carcinogenic potential was observed in preclinical studies. In genotoxicity studies, erlotinib was neither genotoxic nor teratogenic. Long-term carcinogenicity studies in rats and mice have been initiated, and no precancerous proliferative lesions were observed in the 6-month chronic toxicity study.

The genotoxicity of erlotinib was analyzed in a series of in vitro experiments (bacterial mutations, human lymphocyte chromosomal aberrations and mammalian cell mutations) and in vivo mouse bone marrow micronucleus experiments, and no genotoxicity was found.

Erlotinib does not affect the fertility of female and male rats.

When the plasma drug concentration of erlotinib in rabbits reaches approximately 3 times the human plasma concentration (AUC of 150 mg daily), maternal toxicity can occur, leading to embryonic/fetal death and miscarriage. Administration during organogenesis did not increase embryonic/fetal death or miscarriage in rabbits and rats at plasma concentrations reaching approximately human plasma concentrations (based on AUC). However, female rats receiving 30 mg/㎡/d to 60 mg/㎡/d (equivalent to 0.3 to 0.7 times the clinical dose based on mg/㎡) from 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.

Tarceva Pharmacokinetics

There is a lack of data on pharmacokinetic studies in Chinese people. The following information comes from foreign clinical studies.

Erlotinib is approximately 60% absorbed after oral administration, and its bioavailability is significantly increased to almost 100% when taken with food. The half-life is approximately 36 hours, and it is mainly eliminated through CYP3A4 metabolism, and a small amount is eliminated through CYP1A2.

Absorption and Distribution

The bioavailability of Erlotinib is approximately 60% at an oral dose of 150 mg, with peak plasma concentrations reaching 4 hours after administration. Food can significantly increase bioavailability, reaching almost 100%.

After absorption, approximately 93% of erlotinib is bound to albumin and alpha-1 acid glycoprotein (AAG). The apparent volume of distribution of erlotinib is 232 liters.

Metabolism and clearance

In vitro cytochrome P450 analysis showed that erlotinib is mainly metabolized by CYP3A4, and to a small extent by CYP1A2 and extrahepatic isoenzyme CYP1A1. After an oral 100 mg dose, 91% of the drug was recovered, 83% in feces (1% of the dose as unchanged form) and 8% in the urine (0.3% of the dose as unchanged form).

Pharmacokinetic analysis of 591 people taking a single dose of erlotinib showed that the median half-life was 36.2 hours. Therefore, it takes 7 to 8 days to reach steady-state plasma concentrations. There was no significant correlation between clearance rate and age. Erlotinib clearance increased by 24% in smokers.

Special groups

Patients with abnormal liver function

Erlotinib is mainly cleared in the liver. There is currently no data on the effect of abnormal liver function or liver metastasis on the pharmacokinetics of erlotinib. (See [Precautions] - Patients with abnormal liver function, [Adverse Reactions] and [Usage and Dosage] - Dose adjustment).

Patients with abnormal renal function

Urine secretion after a single dose is less than 9%. No clinical trials have been conducted in patients with abnormal renal function.

Interactions

Erlotinib is mainly metabolized by CYP3A4, so it is speculated that inhibitors of CYP3A4 will increase its exposure. When combined with ketoconazole, a strong inhibitor of CYP3A4, the AUC of erlotinib increased by 2/3 (see the dose adjustment section in [Drug Interactions] and [Dosage and Administration]).

Using the CYP3A4 inducer rifampicin before treatment or concurrently can increase the clearance of erlotinib by 3 times and reduce the AUC of erlotinib by 2/3 (see the dose adjustment section in [Drug Interactions] and [Dosage and Administration]).

In a phase Ib clinical trial, there was no significant interaction between the pharmacokinetics of gemcitabine and erlotinib.

Storage of Tarceva

Store at 25℃. Temperatures between 15 and 30℃ are also acceptable.

Medicines should be kept out of the reach of children.