Gefitinib Geftinat

Product Name: Gefitinib Tablets

Common Name: IRESSA

English Name: Gefitinib Tablets

Pinyin: Jifeitini Pian

Specification: 250 mg × 30 tablets/box

Manufacturer: Natco Pharma, India

[IRESSA Indications]

As monotherapy, this product is indicated for the first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumors harbor activating mutations of the epidermal growth factor receptor (EGFR) gene (see [Precautions]).

Results from two large-scale, randomized, controlled clinical trials demonstrated that gefitinib in combination with platinum-based chemotherapy regimens as first-line treatment for locally advanced or metastatic NSCLC showed no clinical benefit; therefore, such combination regimens are not recommended as first-line therapy.

As monotherapy, this product may be used for the treatment of locally advanced or metastatic NSCLC in patients who have previously failed at least one course of chemotherapy (see [Clinical Trials]).

This product is not recommended for use in patients with EGFR wild-type NSCLC.

[IRESSA Dosage and Administration]

The recommended dose of this product is 250 mg (1 tablet) once daily, taken orally, either on an empty stomach or with food. If a dose is missed, the patient should take the missed dose as soon as they remember. If fewer than 12 hours remain before the next scheduled dose, the patient should not take the missed dose. Patients should not take a double dose (two doses at one time) to make up for a missed dose.

When administration of the whole tablet is not possible—for example, if the patient is only able to swallow liquids—the tablet may be dispersed in water. The tablet should be dispersed in half a glass of drinking water (non-carbonated); it does not need to be crushed. Stir until completely dispersed (this takes approximately 15 minutes), and drink the liquid immediately. Rinse the glass with another half-glass of water and drink the rinse liquid. The liquid may also be administered via a nasogastric tube.

Dosage adjustment is not required based on the following factors: age, body weight, gender, race, renal function, or moderate to severe hepatic impairment caused by liver metastases. Dose Adjustment: When patients experience intolerable diarrhea or cutaneous adverse reactions, these may be managed by temporarily withholding treatment (for up to 14 days), followed by resumption at a dose of 250 mg daily (see Adverse Reactions).

Use in Children

There are currently no data regarding the safety and efficacy of this product in pediatric or adolescent patients; therefore, its use is not recommended.

[Iressa Adverse Reactions]

The most common (incidence >20%) adverse drug reactions (ADRs) are diarrhea and skin reactions (including rash, acne, dry skin, and pruritus); these generally occur within the first month of treatment and are usually reversible. Approximately 10% of patients experience severe adverse drug reactions (Grade 3 or 4 according to the National Cancer Institute [NCI] Common Toxicity Criteria [CTC]). Approximately 3% of patients discontinue treatment due to ADRs.

Table 1 lists the classification of the frequency of relevant adverse reactions. These data are derived from the pooled dataset of the Phase III clinical trials ISEL, INTEREST, and IPASS (2,462 patients treated with gefitinib). The frequency classification does not take into account the incidence of adverse events reported in the control groups, nor does it take into account the investigator's assessment of causality with the study drug.

The incidence of adverse reactions associated with laboratory abnormalities is based on patients whose relevant laboratory parameters changed by two or more CTC grades compared to baseline.

Adverse events occurring within each body system are listed in descending order of frequency (Very Common: >10%; Common: >1% and <10%; Uncommon: >0.1% and <1%; Rare: >0.01% and <0.1%; Very Rare: <0.01%).

Table 1: Adverse Reactions Listed by System/Organ and Frequency

**This event may occur concomitantly with other drying reactions associated with this product (primarily dry skin reactions).

**In the pooled analysis of the ISEL, INTEREST, and IPASS studies, the overall incidence of allergic reactions was 1.5% (36 patients). 14 of the 36 patients were excluded from the reported incidence rates because the events were etiologically confirmed not to be allergic reactions, or because the allergic reactions were attributed to other medications.

***Includes individual case reports of hepatic failure, some of which were fatal.

****Based on Phase III clinical studies, the incidence rates for cutaneous vasculitis and hemorrhagic cystitis could not be calculated; since no such adverse reactions were reported in the clinical studies where these events might typically be observed, the incidence rates for these events were estimated based on European Commission guidelines (September 2009)—assuming that 3 such adverse events were reported across the clinical studies involving monotherapy.

Interstitial Lung Disease (ILD)

In a double-blind, Phase III clinical study (ISEL) comparing this product plus Best Supportive Care (BSC) against placebo plus BSC in patients with locally advanced NSCLC (n=1692) who had previously received one or two chemotherapy regimens and whose disease was refractory to or who were intolerant of their most recent treatment, the incidence of ILD-like events was similar in the overall study population, occurring in approximately 1% of patients in both treatment arms. The vast majority of reported ILD-like events occurred within the Asian subgroup; among Asian patients treated with either this product or placebo, the incidence of ILD was similar, at approximately 3% and 4%, respectively. One ILD-like event resulted in death; this occurred in a patient treated with placebo.

In a post-marketing surveillance study conducted in Japan (n=3350 patients), the reported incidence of ILD-like events among patients treated with this product was 5.8%.

In an epidemiological case-control study conducted in Japan among patients with non-small cell lung cancer (NSCLC), the raw cumulative incidence data for ILD during a 12-week follow-up period (unadjusted for imbalances in patient characteristics) showed an incidence of 4.0% in patients treated with this product, compared to 2.1% in patients treated with chemotherapy; relative to chemotherapy, the adjusted odds ratio for developing ILD with this product was 3.2 (95% confidence interval: 1.9–5.4). Compared to chemotherapy, the risk of developing interstitial lung disease (ILD) is elevated with the use of this product; this risk is primarily observed during the first four weeks of treatment (adjusted odds ratio: 3.8; 95% confidence interval: 1.9–7.7), with a lower relative risk thereafter (adjusted odds ratio: 2.5; 95% confidence interval: 1.1–5.8).

In a Phase III open-label clinical trial (IPASS) comparing this product with carboplatin/paclitaxel combination chemotherapy as first-line treatment for selected Asian patients with advanced NSCLC (n=1,217), the incidence of ILD-like events was 2.6% in the gefitinib treatment arm and 1.4% in the carboplatin/paclitaxel treatment arm. Among the Chinese patients enrolled in this study, one ILD-like event occurred in the gefitinib treatment arm (0.5%), while four events occurred in the carboplatin/paclitaxel treatment arm (2.2%).

【Iressa Contraindications】 Patients with a known severe hypersensitivity to the active substance or to any of the excipients contained in this product.

【Iressa Precautions】

When considering this product for the first-line treatment of patients with advanced or metastatic NSCLC, it is recommended that all patients undergo testing for EGFR mutations in their tumor tissue. If the tumor specimen is not evaluable, circulating tumor DNA (ctDNA) obtained from blood (plasma) specimens may be used.

Only validated assay methods capable of accurately determining the EGFR mutation status in tumor tissue or ctDNA should be employed; these methods must be robust, reliable, and sufficiently sensitive to avoid generating false-negative or false-positive results.

Interstitial Lung Disease (ILD)

Cases of interstitial lung disease have been observed in patients receiving treatment with this product; the onset may be acute, and fatal cases have been reported (see [Adverse Reactions]). If a patient experiences worsening respiratory symptoms—such as dyspnea, cough, or fever—treatment with this product should be interrupted, and an immediate investigation should be conducted. If a diagnosis of interstitial lung disease is confirmed, use of this product should be permanently discontinued, and the patient should receive appropriate medical treatment. In an epidemiological case-control study conducted in Japan, 3,159 patients with non-small cell lung cancer (NSCLC) receiving either this product or chemotherapy were followed up for 12 weeks. The following high-risk factors for the development of interstitial lung disease (ILD) were identified (regardless of whether the patient received this product or chemotherapy): smoking, poor performance status (PS ≥ 2), normal lung tissue coverage ≤ 50% on CT scans, short interval since NSCLC diagnosis (< 6 months), pre-existing interstitial pneumonia, advanced age (≥ 55 years), and concomitant cardiac disease. Among patients in both treatment groups who developed ILD, mortality was increased in those presenting with the following risk factors: smoking, reduced normal lung tissue coverage (≤ 50%) on CT scans, pre-existing interstitial pneumonia, advanced age (≥ 65 years), and pleural adhesion at the lesion site (≥ 50%).

Hepatotoxicity

Abnormalities in liver function tests (including elevated alanine aminotransferase [ALT], aspartate aminotransferase [AST], and bilirubin) have been observed (see [Adverse Reactions]); cases presenting as hepatitis have occurred occasionally. Isolated cases of liver failure have been reported, some of which were fatal. Therefore, regular monitoring of liver function is recommended. This product should be used with caution in patients with mild to moderate elevations in liver transaminases. If liver transaminase levels worsen, discontinuation of the drug should be considered.

Severe and Persistent Diarrhea

Patients experiencing severe or persistent diarrhea, nausea, vomiting, or anorexia should be advised to seek immediate medical attention, as these symptoms may indirectly lead to dehydration. These symptoms should be managed according to clinical indications.

Gastrointestinal Perforation

Cases of gastrointestinal perforation have been reported in patients treated with this product; the majority of affected patients possessed other known risk factors (e.g., concomitant use of steroids or non-steroidal anti-inflammatory drugs [NSAIDs]; underlying gastrointestinal disease or ulceration; advanced age; history of smoking; or intestinal metastases at the site of perforation). Ocular Symptoms

Patients presenting with any symptoms or signs suggestive of keratitis (e.g., acute or worsening: eye inflammation, lacrimation, photosensitivity, blurred vision, eye pain, and/or eye redness) should be immediately referred to an ophthalmology specialist.

If ulcerative keratitis is confirmed, treatment with this product should be interrupted; if symptoms do not resolve, or if symptoms recur upon re-administration of Iressa, permanent discontinuation of this product should be considered.

Interactions with Other Drugs

Substances that induce increased CYP3A4 activity may increase the metabolism of this product, thereby reducing its plasma concentrations. Therefore, when this product is used in combination with CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampicin, barbiturates, or St. John's wort), the efficacy of this product may be reduced (see [Drug Interactions]).

Elevated INR (International Normalized Ratio) and/or bleeding events have been reported in some patients taking warfarin (see [Adverse Reactions]). Patients taking warfarin should undergo regular monitoring of prothrombin time or changes in INR.

Drugs that significantly and persistently increase gastric pH may reduce the mean plasma concentrations of gefitinib, thereby potentially reducing the efficacy of gefitinib (see [Drug Interactions]).

In a Phase II clinical study, the concomitant use of this product with vinorelbine suggested that this product may exacerbate the neutropenic effects induced by vinorelbine.

Other

Cerebrovascular events have been reported in clinical trials of this product; however, a causal relationship with this product has not been established.

In a Phase I/II clinical study involving pediatric patients treated with this product and radiotherapy, central nervous system (CNS) hemorrhage occurred in 4 out of 45 enrolled patients (these patients had newly diagnosed brainstem glioma or incompletely resected supratentorial malignant glioma), resulting in 1 fatality. In a clinical study involving monotherapy with this product, a child with ependymoma also experienced CNS hemorrhage. There is no evidence of an increased risk of cerebral hemorrhage in adult NSCLC patients treated with this product. Effects on Ability to Drive and Operate Machinery

During treatment with this product, symptoms of weakness may occur; patients experiencing such symptoms should be advised to exercise caution when driving or operating machinery.

[Iressa: Use in Pregnant and Lactating Women]

Use During Pregnancy

There are currently no data regarding the use of this product in pregnant women. When gefitinib was administered during the period of organogenesis at doses producing maternal toxicity, an increased incidence of incomplete ossification was observed in rats, and a decrease in fetal body weight was observed in rabbits. No malformations were observed in rats; malformations were observed in rabbits only at doses producing severe maternal toxicity. Women of childbearing potential should be advised to avoid pregnancy while undergoing treatment with this product.

Use During Lactation

Lactating mothers should be advised to discontinue breastfeeding while undergoing treatment with this product.

There are currently no data regarding the use of this product in lactating women. It is not known whether gefitinib or its metabolites are excreted in human milk; however, when lactating rats were administered an oral dose of 5 mg/kg gefitinib (approximately 0.2 times the clinical dose based on body surface area), gefitinib and certain metabolites were extensively excreted into the milk.

Administration of gefitinib at a dose of 20 mg/kg/day (approximately 0.7 times the clinical dose based on body surface area) to rats during pregnancy and parturition resulted in a reduction in pup survival rate.

[Iressa: Use in Children]

There are currently no data regarding the safety and efficacy of this product in pediatric or adolescent patients; therefore, its use is not recommended.

[Iressa: Drug Interactions]

In vitro studies using human liver microsomes have confirmed that gefitinib is metabolized primarily via the CYP3A4 isoenzyme of the hepatic cytochrome P-450 system. Therefore, gefitinib may interact with drugs that induce, inhibit, or are metabolized by the same hepatic enzyme. Animal studies have indicated that gefitinib possesses minimal enzyme-inducing activity, while in vitro studies have shown that gefitinib may cause limited inhibition of CYP2D6. The following lists drugs or drug classes that have or may have clinically significant drug interactions with gefitinib:

Drugs Affecting Gefitinib

Established Interactions

Drugs that Inhibit CYP3A4

In healthy volunteers, co-administration of gefitinib with itraconazole (a CYP3A4 inhibitor) resulted in an 80% increase in the mean AUC of gefitinib. Since adverse drug reactions are related to dose and exposure, this increase may be clinically significant. Although interaction studies with other CYP3A4 inhibitors have not been conducted, other drugs in this class—such as ketoconazole, clotrimazole, and ritonavir—may similarly inhibit the metabolism of gefitinib.

Drugs that Increase Gastric pH

A clinical study conducted in healthy volunteers demonstrated that co-administration with ranitidine—at a dose sufficient to significantly and persistently raise gastric pH to ≥5—reduced the mean AUC of gefitinib by 47%; this may reduce the efficacy of gefitinib.

Rifampicin

In healthy volunteers, simultaneous administration of gefitinib with rifampicin (a known potent CYP3A4 inducer) reduced the mean AUC of gefitinib by 83% compared to administration of gefitinib alone.

Theoretically Possible Interactions

Other CYP3A4 Inducers

Substances that induce CYP3A4 activity may increase the metabolism of gefitinib and reduce its plasma concentrations. Therefore, co-administration with CYP3A4 inducers (such as phenytoin, carbamazepine, barbiturates, or St. John's wort) may reduce efficacy.

Effects of Gefitinib on Other Drugs

Established Interactions

Drugs Metabolized via CYP2D6

In a clinical trial, co-administration of gefitinib with metoprolol (a CYP2D6 substrate) resulted in a 35% increase in metoprolol exposure; this was considered to be of no clinical relevance. Co-administration of gefitinib with other drugs metabolized via CYP2D6 may increase the plasma concentrations of the latter. Theoretically Possible Drug Interactions

Warfarin

Although formal drug interaction studies have not been conducted to date, increased INR and/or bleeding events have been reported in some patients taking warfarin.