Generic name: Gefitinib Tablets Trade name: IRESSA English name: Gefitinib Tablets Chinese pinyin: Jifeitini Pian 【Composition】 The main component of this product is Gefitinib, whose chemical name is: N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine. [Properties]: Brown, round, film-coated tablets; printed with “IRESSA 250” on one side. Pharmacological effects】 Liao Dongcheng, Department of Oncology, Huaihua Second People’s Hospital Gefitinib is a selective inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, which is usually expressed in solid tumors of epithelial origin. Gefitinib broadly inhibits the growth and suppresses the angiogenesis of human tumor cells xenografted in nude mice. In vitro, it increases apoptosis in human tumor cell-derived lines and inhibits the invasion and secretion of angiogenic factors. Gefitinib has been shown to enhance the antitumor activity of chemotherapy, radiotherapy and hormonal therapy in animal studies or in vitro studies. Clinical Studies Two large phase II clinical studies evaluated the efficacy and safety of this product as a single agent in the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC). Patients had a WHO physical status score of 0-2 and had to have failed prior chemotherapy : IDEAL1 (Study 0016), received 1 or 2 prior chemotherapy regimens and at least one included platinum-based therapy (median age 59.6 years [28-85 years]; n = 209). IDEAL2 (Study 0039), received 2 or more prior chemotherapy regimens that included concurrent or sequential treatment with platinum and doxorubicin (median age 61 years [30-84 years]; n = 216). The two studies were similar in design, both being double-blind, parallel-group, multicenter, and evaluated two oral doses of gefitinib : 250 mg/day and 500 mg/day. Patients were randomly assigned to these two dose groups. The primary study endpoint in IDEAL1 was objective tumor remission rate and the secondary study endpoint was improvement in disease-related symptoms; in IDEAL2, the primary study endpoint was objective tumor remission rate and improvement in disease-related symptoms (measured weekly by LCS). The efficacy results for IDEAL1 and IDEAL2 are summarized in the table below. Objective tumor remission rates and disease-related symptom improvement rates were similar in both studies, regardless of WHO physical status score (0,1 or 2) and number of prior chemotherapy treatments received. Objective tumor remission occurred in the majority of patients by month 1 of treatment, with a small number of patients experiencing objective remission as late as month 4 of treatment. a In the IDEAL1 trial, the objective remission rate was higher in Japanese patients than in non-Japanese patients for either 250 mg or 500 mg (27.5%:9.6% for 250 mg and 27.5%:11.1% for 500 mg), with an unadjusted ratio (both groups combined) of 3.27, p=0.002. In multivariate analysis, adjusting for gender, histology and physical status at multivariate analysis, this difference was no longer statistically significant (adjusted ratio of 2.13, p=0.068). b Based on symptom improvement assessable population (250 mg, n=67; 500 mg, n=73). + Ongoing at data cut-off. FACT-L quality of life measurement scale for patients with lung cancer. NC not calculated. PFS Progression-free survival. Safety The safety profile of this product was similar in both studies, with a dose-related incidence and severity of adverse events (see “Adverse Reactions”). Conclusion The clinical study data demonstrate that patients with locally advanced or metastatic non-small cell lung cancer can be treated with this product to achieve sustained objective remission. Clinical Study in China A clinical study was conducted at five clinical sites in China to evaluate the objective remission rate of gefitinib 250 mg/day in patients with non-small cell lung cancer who had received prior chemotherapy. A total of 159 subjects received at least one dose of gefitinib tablets 250 mg. The demographic and disease characteristics of the subjects were as follows : 91 males (57.2) and 68 females (42.8); the mean (standard deviation) age was 56.5 years (11.3), the median was 57 years, and the range (minimum, maximum) was 31.0-84.0 years. Age group status : 91 (57.2%) in the 18-60 years group, 46 (28.9%) in the 60-70 years group, and 22 (13.8%) in the over 70 years group. Smoking status: 90 (56.6%) were non-smokers, 37 (23.3%) were former smokers, 3 (1.9%) were occasional smokers, and 29 (18.2%) were regular smokers. Histological classification: squamous carcinoma in 29 (18.2%), adenocarcinoma in 105 (66%), undifferentiated carcinoma in 5 (3.1%), large cell carcinoma in 1 (0.6%), adenosquamous carcinoma in 7 (4.4%), and bronchoalveolar carcinoma (BAC) in 12 (7.5%). Non-small cell lung cancer status at enrollment: 26 (16.4%) with locally advanced MO and 133 (83.6%) with metastatic M1. WHO physical status : 23 (14.5%) had a score of 0, 101 (63.5%) had a score of 1, 34 (21.4%) had a score of 2, and 1 (0.6%) had a score of 3. Among them, 75 subjects (47.2%) had been treated with 1 chemotherapy regimen before enrollment, and 50 (31.4%) and 34 (21.4%) subjects were treated with 2 and 3 or more (including 3) chemotherapy regimens, respectively. Efficacy analysis was performed for 159 subjects (intention-to-treat cohort). The following efficacy summary was performed: objective remission rate of 27.0%, 95% confidence interval of 20.3-34.7%, median PFS of 97 days, 95% confidence interval of 67-120 days, and median survival of 11.1 months (survival data as of November 22, 2004). Objective remission rates showed some variability across treatment subgroups (subjects were grouped according to baseline characteristics at enrollment, and objective remission rates are shown in the table below; similar variability has been seen in other international clinical studies. Although the number of subjects in some subgroups was not large enough, the effect of gefitinib in these subjects was consistent with expectations. Safety] Gefitinib was generally well tolerated. Most adverse events were mild and did not require treatment. Adverse events reported in more than 10% of subjects were rash (44.0%), pruritus (15.7%), and diarrhea (11.3%). The severity and frequency of adverse events observed were consistent with those observed in other clinical studies. Pharmacokinetics】 After intravenous administration, gefitinib was rapidly cleared and widely distributed with a mean clearance half-life of 48 hours. After oral administration to cancer patients, absorption is slower, with a mean terminal half-life of 41 hours. Gefitinib appears to accumulate 2-8 times with 1 daily dose and reaches steady state after 7-10 doses of administration. After steady state is reached, the ratio of maximum to minimum plasma drug concentrations is generally maintained between the 2-3-fold range with 24-hour intervals of dosing. Absorption Following oral administration of this product, peak plasma concentrations of gefitinib occur 3-7 hours after dosing. The mean absolute bioavailability in cancer patients was 59%. The effect of feeding on the absorption of gefitinib was not significant. Distribution The mean volume of distribution of gefitinib at steady state was 1400 L, indicating a wide distribution in tissues. The plasma protein binding rate was approximately 90%. Gefitinib is bound to serum albumin and α1-acidic glycoprotein. Metabolism In vitro data suggest that the P450 isoenzyme involved in the oxidative metabolism of gefitinib is primarily CYP 3A4. In vitro studies show that gefitinib inhibits CYP 2D6 to a limited extent (see “Drug Interactions”). Three sites of biotransformation in the metabolism of gefitinib have been identified: metabolism of the N-propyl morpholine moiety, demethylation of the methoxy substituent on the quinazoline and oxidative defluorination of the halogenated phenyl group class. The main metabolite identified in human plasma was O-demethylgefitinib. It was 14-fold weaker than gefitinib in inhibiting EGFR-stimulated cell growth and is therefore unlikely to have a significant effect on the clinical activity of gefitinib. Elimination The total plasma clearance of gefitinib is approximately 500 mL/min. It is primarily excreted in the feces, with less than 4% being cleared by the kidneys as prototypes and metabolites. Special Populations Population Kinetics : In a population-based analysis of the data, no relationship was found between expected steady-state blood trough concentrations and patient age, weight, sex, race, or creatinine clearance. Hepatic Impairment Gefitinib was evaluated pharmacokinetically in a clinical study involving 31 patients with solid tumors (14 with normal liver function, 13 with moderate liver impairment, and 4 with severe liver impairment due to liver metastases). The time to steady state, total plasma clearance and steady state values (Cmaxss, AUC24SS) were similar between the normal and moderate hepatic impairment groups after 28 days of daily dosing with 250 mg of the drug. 4 patients with severe hepatic impairment due to liver metastases also had steady state values similar to those in the normal hepatic impairment group. This product has not been studied in patients with hepatic impairment caused by cirrhosis or hepatitis. Toxicological studies] Non-clinical (in vitro) data suggest that gefitinib has the potential to inhibit cardiac action potential repolarization processes (e.g., QT interval). However, safety data obtained from clinical studies and post-marketing surveillance do not suggest any adverse cardiac effects of gefitinib. Carcinogenicity, Teratogenicity and Reproductive Toxicity No carcinogenicity studies have been performed with gefitinib. Gefitinib did not show genotoxic effects in mutation analysis (bacterial and in vitro mammalian cells) and lysis assays (in vitro mammalian cells and in vivo rat micronucleus assays). Administration of gefitinib at 20 mg/kg/day (0.7 times the clinical dose based on body surface area) between 4 weeks prior to mating and 7 days of gestation affected ovulation in female rats, resulting in a decrease in luteal volume. When gefitinib was administered at maternally toxic doses during organogenesis, an increased incidence of osteogenesis imperfecta was observed in rats and decreased fetal weight was observed in rabbits. No malformations were observed in rats, and malformations were observed in rabbits only at doses that produced severe maternal toxicity. When 5 mg/kg of gefitinib (0.2 times the clinical dose based on body surface area) was given orally to lactating rats, gefitinib and some metabolites were widely secreted into the milk. Administration of gefitinib at 20 mg/kg/day (0.7 times the clinical dose on a body surface area basis) during gestation and delivery in rats reduced the survival rate of the pups. Indications】 This product is indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) that has received prior chemotherapy. Previous chemotherapy mainly refers to platinum agent and doxorubicin treatment. Efficacy in patients with locally advanced or metastatic non-small cell lung cancer who have failed chemotherapy has been established based on objective response rate metrics, and there are no controlled studies showing clinical benefit in terms of improved disease-related symptoms and prolonged survival. The available data on the use of this product for second-line treatment of non-small cell lung cancer are based on uncontrolled clinical studies only and have yet to be further confirmed in well-designed, controlled clinical trials. For the first-line treatment of non-small cell lung cancer, the results of two large randomized controlled clinical trials have shown no benefit with platinum-based diphtherapy regimens in combination with this product, and therefore gefitinib is not indicated for such treatment. The recommended adult dose of Gefitinib is 250 mg (1 tablet) once daily by mouth, on an empty stomach or with food. If you have difficulty swallowing, disperse the tablet in half a glass of drinking water (not carbonated) and do not use other liquids. Drop the tablet into the water without crushing it, stir until it is completely dispersed (about 10 minutes), and drink the solution immediately. Rinse the glass with half a glass of water and drink. The solution may also be given through a nasogastric tube. No dose adjustment is necessary for age, weight, sex, race, renal function, moderate to severe hepatic impairment due to liver metastases. Dose adjustment: When patients experience intolerable diarrhea or skin reactions, this can be resolved by a short-term suspension of treatment (up to 14 days), followed by resumption of the 250 mg daily dose. Adverse reactions] The most common (over 20% incidence) adverse drug reactions are diarrhea, rash, pruritus, dry skin and acne, usually seen within the first month after dosing, and are usually reversible. Serious adverse drug reactions (CTC criteria grade 3 or 4) occur in approximately 8% of patients. Only 1% of patients discontinued treatment due to adverse reactions. Adverse events by body system were listed in descending order of frequency (common: ≥ (greater than or equal to) 10%; common: ≥ (greater than or equal to) 1% and <10%; rare: ≥ (greater than or equal to) 0.1% and <1%; rare: ≥ (greater than or equal to) 0.1% and <1%; rare: ≥ (greater than or equal to) 0.1% and <1%. (greater than or equal to) 0.01% and <0.1%; very rare: <0.01%). The possible adverse events are summarized as follows: Digestive system: Diarrhea, mainly mild (CTC1 grade), rarely moderate (CTC2 grade), with isolated reports of severe diarrhea with dehydration (CTC3 grade). Nausea, mainly mild (CTC1); vomiting, mainly mild or moderate (CTC1 or 2); anorexia, mild or moderate (CTC1 or 2); oral mucositis, mostly mild (CTC1); dehydrated oral ulcers secondary to diarrhea, nausea, vomiting, or anorexia. Pancreatitis is rare. Skin and adnexa: Skin reactions, mainly mild or moderate (CTC1 or 2); pustular rash, sometimes with dry, itchy skin on top of erythema. Nail abnormalities are common. Very rare reports of toxic epidermal necrolysis and erythema multiforme, allergic reactions, including angioedema and urticaria. Metabolic and nutritional: Abnormalities in liver function are common, mainly including asymptomatic mild or moderate transaminase elevations (CTC1 or grade 2). Systemic: Common weakness, mostly mild (CTC1 level); hair loss; weight loss; peripheral edema. Ophthalmology: Conjunctivitis and blepharitis, mainly mild (CTC1); amblyopia. Reversible corneal erosion, sometimes with abnormal eyelash growth, is rare. Very rare corneal detachment; ocular ischemia/hemorrhage. Hematologic and lymphatic: Bleeding, such as epistaxis and hematuria, is common. Rarely, elevated INR (International Normalised Ratio) and/or bleeding events are seen in some patients taking warfarin; hemorrhagic cystitis. Respiratory: Dyspnea is common. Interstitial lung disease is rare and often severe (CTC grade 3-4. In clinical studies conducted worldwide, expanded dosing/sympathetic dosing, post-marketing use, approximately 158,348 patients were treated with this product, outside of Japan, including approximately 92,821 patients, with an overall incidence of interstitial lung disease of approximately 0.28% and its incidence in Japan of approximately 1.70%, including approximately 65,527 patients, data as of June 2, 2004), and there have been Fatal cases have been reported. [Contraindications] This product is contraindicated in patients with known severe allergic reactions to the active substance or any of the excipients of the product. Precautions] Interstitial lung disease has occasionally been observed in patients treated with this product. Patients usually present with acute dyspnea with cough, hypothermia, respiratory distress and arterial oxygen desaturation. The symptoms can develop severely in the short term, and death has been reported. Radiological examination often shows pulmonary infiltrates or interstitial hairy glassy shadows. A higher mortality rate has been observed in patients presenting with this condition with primary pulmonary fibrosis/interstitial pneumonia/pneumoconiosis/radiolaryngitis/drug-induced pneumonia. Prescribers should closely monitor for signs of the development of interstitial lung disease and interrupt treatment with this product for immediate examination if the patient's respiratory symptoms worsen. When interstitial lung disease is confirmed, the product should be discontinued and the patient should be treated accordingly. Asymptomatic elevations of hepatic transaminases have been observed. Therefore, periodic liver function tests are recommended. This product should be used with caution in patients with mild to moderate elevations in hepatic transaminases. If elevated hepatic transaminases worsen, discontinuation of the drug should be considered. Elevated INR (International Normalised Ratio) and/or bleeding events have been reported in some patients taking warfarin. Patients taking warfarin should be monitored regularly for changes in prothrombin time or INR. Patients should be warned to seek immediate medical attention if any of the following worsen: any ocular symptoms; severe or persistent diarrhea, nausea, vomiting or anorexia; these symptoms should be managed as clinically indicated. Randomized controlled trials have demonstrated no additional benefit from combining this product with a standard two-drug platinum-based combination chemotherapy regimen in patients with advanced non-small cell lung cancer. Therefore, this product should be used alone in patients with non-small cell lung cancer who have received prior cytotoxic chemotherapy. In a phase I/II clinical study of pediatric patients treated with this product and radiotherapy, 4 (1 death) central nervous system hemorrhages occurred in 33 enrolled patients (who had newly diagnosed brainstem gliomas or incompletely resected supratentorial malignant gliomas). In a clinical study treated with this product alone, a child whose patient had a ventricular meningioma also developed CNS hemorrhage. The risk of cerebral hemorrhage is unlikely to be increased in adult patients with non-small cell lung cancer treated with this product. Effects on the ability to drive and operate machinery: Symptoms of weakness may occur during treatment with this product. Patients who develop these symptoms should be cautioned when driving or operating machinery. Use during pregnancy: There is no information on the use of this product in women during pregnancy. An increased incidence of osteogenesis imperfecta was observed in rats and decreased fetal weight was observed in rabbits when gefitinib was given at doses that could produce maternal toxicity during organogenesis. No malformations were observed in rats, and malformations were observed in rabbits only at doses that produced severe maternal toxicity. Women of childbearing potential should be advised to avoid pregnancy during treatment with this product. Use during lactation : Nursing mothers should be advised to discontinue breastfeeding during treatment with this product. There is no information on the use of this product in nursing women. It is not known whether gefitinib or its metabolites are secreted into human milk, but gefitinib and some metabolites are widely secreted into breast milk when 5 mg/kg of gefitinib (0.2 times the clinical dose based on body surface area) is given orally to lactating rats. Administration of gefitinib at 20 mg/kg/day (0.7 times the clinical dose on a body surface area basis) during pregnancy and delivery in rats reduced the survival rate of the pups. Pediatric Use】 There is no information on the safety and efficacy of this product in pediatric or adolescent patients, so its use is not recommended. Drug Interactions】 In vitro tests on human liver microsomes have confirmed that gefitinib is mainly metabolized by CYP 3A4 of the hepatic cytochrome P-450 system. Therefore, gefitinib may interact with drugs that induce, inhibit, or metabolize the same hepatic enzyme. Animal studies have shown that gefitinib has few enzyme-inducing effects, and in vitro studies have shown limited inhibition of CYP 2D6 by gefitinib. The following are the drugs or classes of drugs with which gefitinib interacts or may interact in a clinically meaningful way: Drugs affecting gefitinib: proven interactions - Drugs inhibiting CYP3A4: gefitinib was combined with itraconazole (a CYP 3A4 inhibitor) in healthy volunteers. The mean AUC of gefitinib was increased by 80% when gefitinib was combined with itraconazole (a CYP 3A4 inhibitor) in healthy volunteers. Since adverse drug reactions are dose and exposure dependent, this increase may be clinically significant. Although interactions with other CYP 3A4 inhibitors have not been studied, this class of drugs such as ketoconazole, clotrimazole, and ritonavir may also inhibit the metabolism of gefitinib. Drugs that raise gastric pH: Clinical studies in healthy volunteers have shown that combination with drugs that significantly and consistently raise gastric pH to ≥ (greater than or equal to) 5 reduces the mean AUC of gefitinib by 47%, which may reduce gefitinib efficacy. Rifampin: Concomitant administration of gefitinib with rifampin (a known strong CYP 3A4 inducer) in healthy volunteers reduced the mean AUC of gefitinib by 83% compared to that of gefitinib alone. Drugs that may theoretically interact - other CYP 3A4 inducers: substances that induce CYP 3A4 activity may increase the metabolism of gefitinib and decrease its plasma concentration. Therefore, combination with CYP 3A4 inducers (e.g., phenytoin, carbamazepine, barbiturates, or St. John's wort) may reduce efficacy. Effects of Gefitinib on Other Drugs: Proven Interactions - Drugs Metabolized by CYP 2D6: In a clinical trial, gefitinib combined with metoprolol, a CYP 2D6 enzyme substrate, increased exposure to metoprolol by 35%. Coadministration of gefitinib with other drugs metabolized by CYP 2D6 may elevate blood levels of the latter. Drugs with theoretical potential for interaction - Warfarin : Although no formal drug interaction studies have been performed to date, increased INR and/or bleeding events have been reported in some patients taking warfarin. Patients taking warfarin should be monitored regularly for changes in their prothrombin time or INR. Overdose] There is no specific treatment for overdose of this product and the possible symptoms of overdose are not known at this time. In phase I clinical trials, a small number of patients taking up to 1000 mg per day observed an increased frequency and severity of some adverse reactions, mainly diarrhea and rash. Symptomatic treatment should be given for adverse reactions caused by drug overdose, especially for severe diarrhea, which should be treated appropriately. Specification】 0.25g/tablet 【Storage】 Store below 30°C. Package】 PVC/aluminum foil blister package. 10 tablets/box [Expiration date] 24 months