Date of approval.
Gefitinib Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician.
Drug Name]
Generic name: Gefitinib Tablets
English name: Gefitinib Tablets
Hanyu Pinyin: Jifeitini Pian
Ingredients
The main ingredient of this product is Gefitinib.
Chemical name: N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine
Chemical structure formula.
Molecular formula: C22H24ClFN4O3
Molecular weight: 446.90
Properties
Brown film-coated tablets, white or off-white after removing the coating.
Indications
This single agent is indicated for the first-line 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 (see [Precautions]).
The results of two large randomized controlled clinical trials showed no clinical benefit for gefitinib in combination with platinum-containing chemotherapy regimens for the first-line treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC), so such combinations are not recommended as first-line therapy.
This product alone may be tried for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) that has failed at least one prior chemotherapy.
It is not recommended for use in patients with EGFR wild-type non-small cell lung cancer.
Specification
0.25g.
Dosage]
The recommended dose of this product is 250mg (1 tablet) once a day, taken orally on an empty stomach or with food. If you miss one dose of this product, you should take it as soon as the patient remembers. If it is less than 12 hours before the next dose, the patient should not take the missed dose. Patients should not take double the dose (twice the dose in one dose) to make up for a missed dose.
When the entire tablet cannot be administered, such as when the patient can only swallow liquids, the tablet may be dispersed in water. The tablet should be dispersed in half a glass of drinking water (not carbonated) without crushing, stirred until completely dispersed (about 15 minutes), and drunk immediately. Rinse the glass with half a glass of water and drink the solution. The solution can 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 may be resolved by a short-term suspension (up to 14 days) followed by resumption of the 250 mg daily dose (see [ADVERSE REACTIONS]).
Use in Children
There is no information on the safety and efficacy of this product for use in pediatric or adolescent patients; therefore, its use is not recommended.
Adverse reactions
The most common (over 20% incidence) adverse drug reactions (ADRs) are diarrhea and skin reactions (including rash, acne, dry skin, and pruritus), usually within the first month of administration, and are usually reversible. Serious adverse drug reactions (according to the National Cancer Institute [NCI] Common Toxicity Criteria [CTC] grade 3 or 4) occur in approximately 10% of patients. Approximately 3% of patients discontinued treatment due to ADRs.
A classification of the frequency of relevant adverse reactions is presented in Table 1 from the pooled data set of the phase III clinical trials ISEL, INTEREST, and IPASS (2462 gefitinib-treated patients). The classification of frequency did not take into account the incidence of adverse events reported by the control group and did not take into account the correlation with the trial drug as judged by the investigator.
The incidence of adverse reactions associated with abnormal laboratory tests was based on patients with a change in the relevant laboratory index of 2 CTC levels or more from baseline.
Adverse reactions occurring in each body system are listed in descending order of frequency (very common: >10%; common: >1% and <10%; occasional: >0.1% and <1%; rare: >0.01% and <0.1%; very rare: <0.01%).
Table 1: Adverse reactions by system/organ and incidence
Digestive system: Very common diarrhea, mainly mild or moderate (CTC1 or 2), rarely severe (CTC3 or 4)
Nausea, mainly mild (CTC1)
Vomiting, mainly mild or moderate (CTC1 or 2)
Stomatitis, mostly mild (CTC1) commonly secondary to dehydration with diarrhea, nausea, vomiting or anorexia
Dry mouth*, mainly mild (CTC1 level) Occasionally pancreatitis, GI perforation Hepatobiliary system/very common elevated alanine aminotransferase, mainly mild to moderate Common elevated aspartate aminotransferase, mainly mild to moderate
Total bilirubin elevation, mainly mild to moderate Occasional hepatitis*** Skin and subcutaneous tissue abnormalities: Very common skin reaction, mainly mild or moderate (CTC grade 1 or 2) Pustular rash, sometimes with dry, itchy and cracked skin on top of erythema Common nail abnormalities
Alopecia Occasional allergic reactions**, including angioedema and urticaria Rare maculopapular conditions, including toxic epidermal necrolysis relaxans, Stevens- Johnson syndrome and erythema multiforme Cutaneous vasculitis **** Metabolic and nutritional disorders/very common anorexia, mild or moderate (CTC grade 1 or 2) Systemic disease and administration site reactions/very common weakness, mostly mild (CTC grade 1) Common fever Ophthalmology: common conjunctivitis, blepharitis and dry eyes*, mostly mild (CTC grade 1) Occasionally reversible corneal erosions, sometimes with abnormal eyelash growth
Keratitis (0.12%) Vascular system: common bleeding, such as rhinorrhea and hematuria Respiratory: common interstitial lung disease (ILD), often severe (CTC grade 3-4), with fatal cases reported Renal and urinary system: common asymptomatic elevated blood creatinine lab values.
Proteinuria
Cystitis rare hemorrhagic cystitis ***** This event can occur in conjunction with other drying reactions to this product (mainly skin drying reactions).
**The overall incidence of allergic reactions in the pooled analysis of the ISEL, INTEREST, and IPASS studies was 1.5% (36 patients). 14 of the 36 patients were excluded from the reported incidence because, either these reports were etiologically proven not to be allergic reactions or their allergic reactions were due to other drugs.
***Includes individual reports of liver failure, some of which were fatal cases.
**** has not been able to calculate the incidence of cutaneous vasculitis and hemorrhagic cystitis based on phase III clinical studies because no such adverse reactions were reported in these clinical studies where relevant events might be observed; therefore, the incidence of these events was extrapolated from the European Commission guidelines (September 2009) – assuming that three such adverse events were reported in clinical studies of monotherapy.
Interstitial Lung Disease
In a double-blind phase III clinical study (ISEL) comparing this product plus best supportive care (BSC) with placebo plus BSC in patients with locally advanced NSCLC who had received one or two prior chemotherapy regimens and were ineffective or intolerant to the most recent treatment (1692 patients), the incidence of interstitial lung disease-type events was similar in the overall population and was approximately 1% in both treatment groups. The vast majority of reported interstitial lung disease-type events were from Asian populations, and the incidence of interstitial lung disease was similar in patients from Asian populations treated with this product or placebo, at approximately 3 and 4 percent, respectively. One interstitial lung disease-type event resulted in death, in a patient treated with placebo.
In a post-marketing drug monitoring study in Japan (3350 patients), the reported incidence of interstitial lung disease-type events in patients treated with this product was 5.8%.
In an epidemiologic case-control study in patients with non-small cell lung cancer in Japan, the raw data on the cumulative incidence of interstitial lung disease over a 12-week follow-up period (not adjusted for imbalances in patient characteristics) were 4.0% for patients receiving this product and 2.1% for patients receiving chemotherapy; the corrected ratio for the occurrence of interstitial lung disease treated with this product compared with chemotherapy was 3.2 ( The 95% confidence interval was 1.9-5.4). The increased risk of interstitial lung disease with this product relative to chemotherapy was seen primarily in the first four weeks of treatment (corrected ratio of 3.8, 95% confidence interval 1.9-7.7), with a lower relative risk thereafter (corrected ratio of 2.5, 95% confidence interval 1.1-5.8).
In a phase III open clinical trial comparing this product with carboplatin/paclitaxel duo chemotherapy for first-line treatment-selective advanced NSCLC in Asian patients (1217 patients) (IPASS), the incidence of ILD-type events was 2.6% in the gefitinib-treated arm and 1.4% in the carboplatin/paclitaxel-treated arm. Among Chinese patients in this clinical study, one ILD-type event occurred in the gefitinib-treated group (0.5%) and four in the carboplatin/paclitaxel-treated group (2.2%).
[Contraindicated].
Persons with known severe allergic reactions to the active substance or to any of the excipients of the product.
[Precautions].
When considering this product for first-line treatment of patients with advanced or metastatic NSCLC, EGFR mutation testing of tumor tissue is recommended for all patients. If tumor specimens are not evaluable, circulating tumor DNA (ctDNA) obtained from blood (plasma) specimens may be used.
Only assays that have been validated for determining the EGFR mutation status of the tumor or ctDNA should be used, and the assay must be stable, reliable, and sensitive to avoid false-negative or false-positive results.
Interstitial Lung Disease
Interstitial lung disease has been observed in patients treated with this product and may occur acutely, with reports of death (see [ADVERSE REACTIONS]). If the patient’s respiratory symptoms worsen, such as dyspnea, cough, and fever, treatment with this product should be interrupted and examined immediately. When interstitial lung disease is confirmed, the product should be discontinued and the patient should be treated accordingly.
In an epidemiologic case-control study conducted in Japan with a 12-week follow-up of 3159 patients with non-small cell lung cancer who received this product or chemotherapy, the following high-risk factors for the development of interstitial lung disease were identified (regardless of whether the patient received this product or chemotherapy): smoking, poor physical status (PS ≥ 2), ≤ 50% coverage of normal lung tissue on CT scan, distance to non-small cell lung cancer diagnosis was short (<6 months), pre-existing interstitial pneumonia, older age (≥ 55 years), and concomitant cardiac disease.
Patients in both treatment groups who developed ILD had increased mortality if they had the following risk factors: smoking, ≤50% reduction of normal lung tissue on CT scan, pre-existing interstitial pneumonia, older age (≥ 65 years), and adhesions of the lesion to the pleura (≥ 50%).
Hepatotoxicity
Abnormal liver function tests (including elevated alanine aminotransferase, elevated aspartate aminotransferase, and elevated bilirubin) have been observed (see [ADVERSE REACTIONS]), with occasional manifestations of hepatitis. Individual cases of liver failure have been reported, some of which were fatal. 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.
Severe and persistent diarrhea
Patients should be cautioned to seek immediate medical attention when they present with severe or persistent diarrhea, nausea, vomiting or anorexia, as all of these symptoms may indirectly cause dehydration. These symptoms should be treated as clinically indicated
Gastrointestinal perforation
Gastrointestinal perforation has been reported in patients treated with this product, and most patients involved include other known risk factors (e.g., concomitant steroids, NSAIDs; underlying GI disease, ulcers, age, history of smoking, metastatic tumors in the intestinal tract at the site of perforation).
Ocular symptoms
Presence of any sign or symptom suggestive of keratitis (e.g., acute or exacerbation of.
ocular inflammation, tearing, light sensitivity, blurred vision, ocular pain and/or ocular redness) should be referred immediately to an ophthalmologist.
If ulcerative keratitis is diagnosed, treatment with this product should be discontinued; permanent discontinuation of treatment with this product should be considered if there is no relief of symptoms or if symptoms recur on reintroduction of Erythroxa.
Interactions with other drugs
Substances that induce increased CYP3A4 activity can increase the metabolism of this product and decrease the plasma concentration of this product. Therefore, when this product is used in combination with CYP3A4-inducing substances (e.g., phenytoin, carbamazepine, rifampin, barbiturates, or St. John’s wort), the efficacy of this product may be reduced (see [Drug Interactions]).
Elevated INR (International Normalised Ratio) and/or bleeding events have been reported in some patients taking warfarin (see [Adverse Reactions]). Patients taking warfarin should be monitored regularly for changes in prothrombin time or INR.
Drugs that significantly and consistently increase gastric pH may decrease the mean plasma concentration of gefitinib and thus may decrease the efficacy of gefitinib (see [Drug Interactions]).
In phase II clinical studies, concomitant use of this product with vincristine showed that this product may exacerbate the effects of vincristine-induced neutropenia.
Other
Cerebrovascular events have been reported in clinical trials with this product, but the relationship to this product was not determined.
In a phase I/II clinical study of pediatric patients treated with this product and radiotherapy, 4 (1 death) CNS hemorrhages occurred in 45 enrolled patients (who were newly diagnosed brainstem gliomas or incompletely resected supratentorial malignant gliomas)
. In a clinical study treated with this product alone, a child with a ventricular meningioma also developed CNS hemorrhage. There was no evidence of an increased risk of cerebral hemorrhage in adult NSCLC patients treated with this product.
Effects on the ability to drive and operate machinery
Symptoms of weakness may occur during treatment with this product, and patients who develop these symptoms should be cautioned when driving or operating machinery.
Pregnant women and nursing mothers
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
During treatment with this product
Nursing mothers should be advised to discontinue breastfeeding.
There is no information on the use of this product in nursing mothers. It is not known whether gefitinib or its metabolites are secreted into human milk, but gefitinib and some of its metabolites are widely secreted into milk when given orally to lactating rats at 5 mg/kg of gefitinib (0.2 times the clinical dose based on body surface area).
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 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.
Geriatric use
See [Dosage and Administration].
Drug Interactions
In vitro tests on human liver microsomes have shown that gefitinib is mainly metabolized by CYP3A4 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 little enzyme induction by gefitinib, and in vitro studies have shown limited inhibition of CYP2D6 by gefitinib.
The following is a list of drugs or classes of drugs that have or may have clinically meaningful drug interactions with gefitinib.
Drugs affecting gefitinib
Proven interactions
Drugs that inhibit CYP3A4
Combining gefitinib with itraconazole (a CYP3A4 inhibitor) in healthy volunteers increased the mean AUC of gefitinib by 80%. Since adverse drug reactions are dose and exposure related, this elevation may be clinically significant. Although interaction studies with other CYP3A4 inhibitors have not been conducted, this class of drugs such as ketoconazole, clotrimazole, and Ritonovir may also inhibit gefitinib metabolism.
Drugs that elevate gastric pH
A clinical study in healthy volunteers showed that combination with ranitidine at doses that significantly and consistently raised gastric pH to ≥5 reduced the mean AUC of gefitinib by 47%, which may reduce gefitinib efficacy.
Rifampin
Co-administration of gefitinib with rifampicin (a known strong CYP3A4 inducer) in healthy volunteers reduced the mean AUC of gefitinib by 83% compared to that of gefitinib alone.
Drugs with theoretical possible interactions
Other CYP3A4 inducers
Substances that induce CYP3A4 activity may increase the metabolism of gefitinib and decrease its plasma concentration. Therefore, combination with CYP3A4-inducing agents (e.g., phenytoin, carbamazepine, barbiturates, or St. John’s wort) may reduce efficacy.
Gefitinib’s effects on other drugs
Proven interactions
Drugs metabolized via CYP2D6
In a clinical trial, gefitinib in combination with metoprolol (a CYP2D6 enzyme substrate) increased exposure to metoprolol by 35%, which was not considered clinically relevant. Coadministration of gefitinib with other drugs metabolized by CYP2D6 may elevate blood levels of the latter.
Drugs that may theoretically interact
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 periodically for changes in their prothrombin time or INR (see [Precautions]).
Vincristine
In phase II clinical studies, concomitant administration of this product with vincristine showed that this product may exacerbate the neutropenic effect caused by vincristine.
Drug overdose]
There is no specific treatment for overdose of this product. Symptomatic treatment should be given for adverse reactions caused by drug overdose, especially severe diarrhea should be managed according to clinical indications. In phase I clinical trials, a small number of patients received doses up to 1000 mg per day and an increased frequency and severity of some adverse reactions, mainly diarrhea and rash, were observed. A small number of patients in one study received doses of 1500 mg to 3500 mg per week. Gefitinib exposure in this study did not increase with dose and adverse reactions were primarily mild to moderate in severity, consistent with the known safety profile of gefitinib.
Pharmacology and Toxicology]
Pharmacological effects
The epidermal growth factor receptor (EGFR) is expressed in both normal and tumor cells and plays an important role in the growth and differentiation of cells. EGFR mutations (exon 19 deletion and exon 21 L858R mutation) in non-small cell lung cancer cells can promote tumor cell growth, inhibit apoptosis, increase angiogenic factor production, and promote tumor metastasis.
Gefitinib, a reversible inhibitor of wild-type and certain mutant EGFR, inhibits autophosphorylation of EGFR receptor tyrosine, which further inhibits downstream signaling and prevents EGFR-dependent cell proliferation.
Gefitinib has a greater affinity for mutant EGFR (exon 19 deletion and exon 21 L858R mutation) than for wild-type EGFR. Gefitinib also inhibits IGF and PDGF-mediated signaling at clinically relevant concentrations; the inhibitory effect of gefitinib on other tyrosine kinases is not known.
Toxicological studies
Genotoxicity
Gefitinib was negative in in vitro (bacterial, mouse lymphoma and human lymphocyte) and rat micronucleus assays.
Reproductive toxicity
In a specific fertility test in rats, an increased incidence of estrus disorders, a decrease in the number of corpus luteum, and a decrease in the number of live fetuses per litter and in uterine fertility were observed at doses of gefitinib ≥120 mg/m2 (comparable to clinical doses based on body surface area).
Oral administration of gefitinib at 20 mg/kg/day (0.7 times the clinical dose in terms of body surface area) during pregnancy and delivery in rats resulted in reduced pup survival.
In animal reproductive toxicity tests, oral administration of gefitinib at doses lower than the clinical dose from organogenesis to lactation caused embryotoxicity and neonatal mortality. Gefitinib given at 5 mg/kg from organogenesis to weaning in pregnant rats resulted in fewer surviving neonates; toxicity was more severe at a dose of 20 mg/kg (roughly equivalent to the clinical dose based on body surface area), with an increased proportion of pups dying after birth. In rabbits, gefitinib at 20 mg/kg/day (240 mg/m2, approximately twice the clinical dose on a body surface area basis) reduced fetal body weight.
In rats given a single oral dose of gefitinib 5 mg/kg (approximately 0.2 times the clinical dose based on body surface area), gefitinib was transmissible through the placenta; gefitinib and some metabolites were widely secreted into breast milk.
Carcinogenicity
In a two-year mouse carcinogenicity study, hepatocellular adenomas were seen in females at a dose of gefitinib of 270 mg/m2/day (reduced from 375 mg/m2/day starting at week 22, approximately twice the clinical dose on a body surface area basis). In a two-year rat carcinogenicity study, hepatocellular adenomas and mesenteric lymph node hemangiomas/angiosarcomas were seen in females at a dose of 60 mg/m2/day (approximately 0.4 times the clinical dose on a body surface area basis). The clinical relevance of these findings is not known.
Pharmacokinetics]
After intravenous administration, gefitinib is 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 reaches steady state after 7-10 doses administered once daily, with 2-8-fold accumulation occurring. After reaching steady-state, 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, peak plasma concentrations of gefitinib occur 3 to 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 CYP3A4.
In vitro studies have shown limited inhibition of CYP2D6 by gefitinib (see [Drug Interactions]).
Gefitinib did not show enzyme-inducing effects in animal studies.
There was also no significant inhibition of other cytochrome P450 enzymes in vitro.
Three sites of biotransformation have been identified in the metabolism of gefitinib: metabolism of the N-propyl morpholine group, demethylation of the methoxy substituent on quinazoline and oxidative defluorination of the halogenated phenyl group class. Five metabolites have been fully identified in feces, the major metabolite being O-desmethylgefitinib, although it represents only 14% of the dose.
Eight metabolites have been fully identified in human plasma, and the major metabolite is O-desmethylgefitinib. It was 14-fold weaker than gefitinib in inhibiting EGFR-stimulated cell growth and had no inhibitory effect on tumor cell growth in mice. It is therefore considered unlikely to have a role in the clinical activity of gefitinib.
In vitro studies suggest that CYP2D6 is involved in the production of O-demethylgefitinib. The role of CYP2D6 in the metabolic clearance of gefitinib has been evaluated in clinical studies in healthy volunteers typed by CYP2D6 status. No measurable levels of O-demethylgefitinib were produced in slow metabolizers. The range of gefitinib exposures was very large and overlapping in both fast and slow metabolizers, but the mean exposure to gefitinib was 2-fold higher in the slow metabolizers than in the fast metabolizers. Since adverse effects are dose and exposure dependent, the high mean exposure achieved in individuals lacking active CYP2D6 may be clinically relevant.
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 population-based data analyses performed in cancer patients, no relationship was found between expected steady-state blood trough concentrations and patient age, weight, gender, race, or creatinine clearance.
Liver Function Impairment
In a phase I open study, exposure levels were elevated in all groups following a single dose of 250 mg gefitinib in patients with mild, moderate or severe hepatic impairment due to cirrhosis (according to Child-Pugh classification) compared to healthy subject controls. In patients with moderate and severe hepatic impairment, gefitinib exposure levels were elevated by a mean of 3.1-fold. None of these patients had cancer, but all were patients with cirrhosis, and some had hepatitis. This elevated level of exposure may be clinically relevant as adverse effects are associated with dose and exposure to gefitinib.
Gefitinib was evaluated pharmacokinetically in a clinical study involving 41 patients with solid tumors (those with normal liver function, those with moderate liver impairment, and those who developed severe liver impairment due to liver metastases). The study showed that 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 this product. The steady-state values of four patients who developed severe hepatic impairment due to liver metastasis were also similar to those of the normal liver function group.
Storage
Store below 30℃.
Package
Aluminum-plastic packaging. 10 tablets/plate: 10 tablets/box, 30 tablets/box, 50 tablets/box; 7 tablets/plate: 7 tablets/box, 21 tablets/box, 35 tablets/box.
[Expiration date
24 months
【Execution standard
【Approval number】
【Manufacturing enterprise
Company Name: Qilu Pharmaceutical (Hainan) Co.
Production Address: No. 273, Nanhai Avenue, Haikou National High-tech Zone, Haikou City, China
Postal Code: 570314
Telephone number: 0898-68629588
Fax number: 0898-68629588
Web address: http://www.qilu-hainan.com