Geftib gefitinib 250mg

Indications: This product is indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy. Previous chemotherapy primarily refers to treatment with platinum-based agents and docetaxel.

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.

Adverse Reactions:

The most common adverse drug reactions (ADRs) (incidence > 20%) 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.

This product is indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy. Previous chemotherapy primarily refers to treatment with platinum-based agents and docetaxel.

The efficacy of this product in patients with locally advanced or metastatic NSCLC who have previously received chemotherapy was established based on survival benefits observed in a pre-specified Asian subgroup within a large-scale placebo-controlled clinical trial (Note: In the overall population of this trial, no improvement in disease-related symptoms or prolongation of survival was demonstrated), as well as on survival data from uncontrolled clinical trials conducted in China.

Results from two large-scale randomized controlled clinical trials indicate that gefitinib in combination with platinum-based chemotherapy regimens as first-line treatment for locally advanced or metastatic NSCLC did not demonstrate clinical benefit; therefore, such combination regimens are not recommended.

[Specification] 0.25 g

[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 swallowing is difficult, the tablet may be dispersed in half a glass of drinking water (non-carbonated). No other liquids should be used. Drop the tablet into the water (do not crush it) and stir until completely dispersed (this takes approximately 10 minutes); drink the liquid immediately. Rinse the glass with another half-glass of water and drink it. The liquid may also be administered via a nasogastric tube. No dosage adjustment is required based on the following factors: age, body weight, gender, race, renal function, or moderate to severe hepatic impairment caused by liver metastases.

Dosage Adjustment: When patients experience intolerable diarrhea or cutaneous adverse reactions, these may be managed by temporarily interrupting treatment (for up to 14 days), followed by resumption of the 250 mg daily dose (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.

[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 typically reversible. Approximately 8% of patients experience severe adverse drug reactions (CTC Grade 3 or 4). Treatment discontinuation due to ADRs occurs in approximately 3% of patients.

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%).

Based on data from global clinical studies, expanded access/compassionate use programs, and post-marketing surveillance, the overall estimated reporting rate for interstitial lung disease (ILD) is approximately 0.3% in regions outside of Japan, and approximately 3% in Japan.

In a double-blind, Phase III clinical study comparing this product plus Best Supportive Care (BSC) against placebo plus BSC—conducted in patients with locally advanced NSCLC 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 across the overall study population, occurring in approximately 1% of patients in each treatment arm. The vast majority of reported interstitial lung disease (ILD)-like events occurred in Asian populations; among Asian patients treated with this product or placebo, the incidence of ILD was similar, occurring in approximately 3% and 4% of patients, 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 (involving 3,350 patients), the reported incidence of ILD-like events in patients treated with this product was 5.8%.

**[Contraindications]**

Patients with known severe hypersensitivity to the active substance or to any of the excipients of this product.

**[Precautions]**

Interstitial lung disease has been observed in patients treated with this product; onset may be acute. Patients typically present with acute dyspnea, accompanied by cough, low-grade fever, respiratory discomfort, and arterial hypoxemia. These symptoms may progress rapidly in severity over a short period, and cases of death have been reported. Radiological examinations often reveal pulmonary infiltrates or ground-glass opacities in the interstitium. It has been observed that among patients who develop this condition, mortality rates are higher in those with underlying pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonitis, or drug-induced pneumonia.

Prescribing physicians should closely monitor for signs of interstitial lung disease. If a patient's respiratory symptoms worsen, treatment with this product should be interrupted, and an immediate investigation should be conducted. If interstitial lung disease is confirmed, use of this product should be permanently discontinued, and the patient should receive appropriate treatment.

Elevations in liver transaminases have been observed (see *Adverse Reactions*), with rare cases presenting as hepatitis. Therefore, periodic 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.

Elevations in 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 changes in prothrombin time or INR.

Patients should be advised to seek immediate medical attention if the following conditions worsen:

Any ocular symptoms;

Severe or persistent diarrhea, nausea, vomiting, or anorexia.

These symptoms should be managed as clinically indicated (see Adverse Reactions).

Randomized controlled trials have demonstrated that, in patients with advanced non-small cell lung cancer (NSCLC), the combination of this product with standard platinum-based doublet chemotherapy regimens provides no additional benefit. Therefore, this product should be used as monotherapy in patients with NSCLC who have previously received cytotoxic chemotherapy.

In a Phase I/II clinical study evaluating this product in combination with radiotherapy in pediatric patients, 4 cases of central nervous system (CNS) hemorrhage (including 1 fatality) occurred among the 45 enrolled patients (who had newly diagnosed brainstem glioma or incompletely resected supratentorial malignant glioma). In a clinical study involving monotherapy with this product, a child with ependymoma also experienced CNS hemorrhage. The risk of cerebral hemorrhage is unlikely to be increased in adult NSCLC patients receiving treatment with this product.

Effects on Ability to Drive and Use Machines

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

[Use in Pregnancy and Lactation]

Use in Pregnancy: Women of childbearing potential should be advised to avoid pregnancy while undergoing treatment with this product.

Use in Lactation: Nursing mothers should be advised to discontinue breastfeeding while undergoing treatment with this product.

[Use in Children]

Currently, there are no data available regarding the safety and efficacy of this product in pediatric or adolescent patients; therefore, its use is not recommended. [Geriatric Use]

Refer to "Dosage and Administration."

[Drug Interactions]

In vitro studies using human liver microsomes have confirmed that gefitinib is primarily metabolized via the hepatic cytochrome P-450 system, specifically CYP3A4. Therefore, gefitinib may interact with drugs that induce, inhibit, or are metabolized by the same hepatic enzymes. Animal studies indicate that gefitinib has minimal enzyme-inducing activity, while in vitro studies suggest that gefitinib may cause limited inhibition of CYP2D6.

The following lists drugs or drug classes that have been shown to produce, or may potentially produce, clinically significant drug interactions with gefitinib:

Drugs Affecting Gefitinib

Established Interactions:

CYP3A4 Inhibitors

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 both 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

Clinical studies conducted in healthy volunteers indicate that co-administration with drugs capable of significantly and persistently raising gastric pH to ≥ 5 results in a 47% decrease in the mean AUC of gefitinib; this may lead to reduced efficacy of gefitinib.

Rifampicin

In healthy volunteers, simultaneous administration of gefitinib with rifampicin (a known potent inducer of CYP3A4) resulted in an 83% decrease in the mean AUC of gefitinib compared to administration of gefitinib alone.**Theoretically Possible Drug 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 enzyme substrate) resulted in a 35% increase in metoprolol exposure; this was considered not to be clinically relevant. 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. Patients taking warfarin should have their prothrombin time or INR monitored regularly (see *Precautions*).

**Vinorelbine**

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

**[Overdosage]**

There is no specific treatment for overdosage of this product, and the potential symptoms of overdosage are currently unknown. In Phase I clinical trials, a small number of patients received doses up to 1000 mg per day; an increased frequency and severity of certain adverse reactions—primarily diarrhea and skin rash—were observed. Adverse reactions resulting from drug overdose should be managed symptomatically; in particular, severe diarrhea should be treated appropriately.

[Pharmacological Actions]

Gefitinib is a selective inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase, an enzyme typically expressed in solid tumors of epithelial origin.

Gefitinib broadly inhibits the growth of human tumor cells xenografted into nude mice and suppresses their angiogenesis; *in vitro*, it enhances apoptosis in human tumor cell lines and inhibits the invasion and secretion of angiogenic factors. Animal studies and *in vitro* investigations have demonstrated that gefitinib can augment the anti-tumor activity of chemotherapy, radiotherapy, and hormonal therapy.

[Pharmacokinetics]

Following intravenous administration, gefitinib is rapidly cleared and widely distributed, with an average elimination half-life of 48 hours. Following oral administration in cancer patients, absorption is relatively slow, and the average terminal half-life is 41 hours. With once-daily dosing, gefitinib accumulates 2- to 8-fold, reaching steady-state concentrations after 7 to 10 doses. Once steady-state is achieved, with a 24-hour dosing interval, the ratio of the peak to trough plasma drug concentrations generally remains within the range of 2- to 3-fold.

Absorption

Following oral administration of this product, peak plasma concentrations of gefitinib are observed between 3 and 7 hours post-dosing. The mean absolute bioavailability in cancer patients is 59%. Food intake does not have a significant effect on the absorption of gefitinib.

Distribution

At steady-state, the mean volume of distribution for gefitinib is 1400 L, indicating extensive distribution into tissues. Plasma protein binding is approximately 90%. Gefitinib binds to serum albumin and alpha-1 acid glycoprotein. Metabolism

*In vitro* data indicate that the primary P450 isoenzyme involved in the oxidative metabolism of gefitinib is CYP3A4.

*In vitro* studies have shown that gefitinib can cause limited inhibition of CYP2D6 (see Drug Interactions).

In animal studies, gefitinib did not demonstrate enzyme-inducing effects, nor did it exhibit significant inhibitory effects on other cytochrome P450 enzymes *in vitro*.

Three sites of biotransformation have been identified in the metabolism of gefitinib: metabolism of the N-propylmorpholino group, O-demethylation of the methoxy substituent on the quinazoline ring, and oxidative defluorination of the halogenated phenyl group. Five metabolites have been fully identified in feces; the major metabolite is O-desmethyl gefitinib, although it accounts for only 14% of the administered dose.

Eight metabolites have been fully identified in human plasma; the major metabolite is O-desmethyl gefitinib. Its inhibitory effect on EGFR-stimulated cell growth is 14 times weaker than that of gefitinib, and it exhibits no inhibitory activity against mouse tumor cell growth. Consequently, it is considered unlikely to contribute to the clinical activity of gefitinib.

*In vitro* studies indicate that CYP2D6 is involved in the formation of O-desmethyl gefitinib. The role of CYP2D6 in the metabolic clearance of gefitinib was evaluated in a clinical study involving healthy volunteers genotyped for CYP2D6 status. In poor metabolizers, measurable levels of O-desmethyl gefitinib were not produced. While the range of gefitinib exposure was highly variable and overlapping in both rapid and poor metabolizer populations, the mean exposure to gefitinib in poor metabolizers was approximately twofold higher than that in rapid metabolizers. Since adverse reactions are correlated with dose and exposure, the higher mean exposure levels attained in individuals lacking active CYP2D6 may be of clinical relevance. Elimination

The total plasma clearance of gefitinib is approximately 500 mL/min. It is primarily excreted via the feces; less than 4% is eliminated via the kidneys, in the form of both the parent compound and its metabolites.

[Chemical Composition] Chemical Name: N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine

[Description] Brown, round, film-coated tablets; imprinted with "IRESSA 250" on one side.

[Storage] Store below 30°C.

[Packaging] PVC/aluminum foil blister packaging. 30 tablets per box.

[Shelf Life] 24 months

Product Specifications

Product Name: IRESSA (Gefitinib) | Geftib gefitinib 250mg

Common Name: IRESSA

Composition: Gefitinib 250mg

Dosage Form: Tablets

Specification: 30 tablets