Geftinat

Gefitinib (Iressa) instructions

Common name: Gefitinib

Trade name: Iressa

All names: Gefitinib, Iressa, Gefitinib, Ires sa, Geftinat

Indications of Gefitinib

This product is suitable for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) that has previously received chemotherapy. Previous chemotherapy treatments mainly referred to platinum and docetaxel treatments.

The efficacy of this product for patients with locally advanced or metastatic non-small cell lung cancer who have previously received chemotherapy was established based on the survival advantage of the Asian subgroup in a large-scale placebo-controlled clinical trial (note: the trial did not show improvement in disease-related symptoms and prolonged survival in the overall population) and survival data from uncontrolled clinical trials in China.

The results of two large randomized controlled clinical trials showed that gefitinib combined with platinum-containing chemotherapy regimens showed no clinical benefit in the first-line treatment of locally advanced or metastatic NSCLC, so such combination regimens are not recommended.

Gefitinib usage and dosage

The recommended dose is 250 mg (1 tablet) once a day, on an empty stomach or with food. Not recommended for use in children or adolescents, safety and efficacy have not been studied in this patient population. No dose adjustment is required based on the patient's age, weight, sex, or renal function status and in patients with moderate or severe hepatic impairment due to liver metastasis from tumors.

Gefitinib Adverse Reactions

The most common adverse drug reactions (ADRs) are diarrhea, rash, itching, dry skin and acne, with an incidence rate of more than 20%. They generally occur within one month after taking the drug and are usually reversible. Approximately 8% of patients developed severe ADRs (CTC criteria grade 3 or 4). Only 1% of patients discontinued treatment due to ADRs.

The possible adverse drug reactions are summarized as follows:

Very common (>10%)

Digestive system: Skin and appendages: Diarrhea, mainly mild (CTC grade 1), rarely moderate (CTC grade 2), with individual reports of severe diarrhea accompanied by dehydration (CTC grade 3). Nausea, mainly mild (CTC grade 1). Skin reactions are mainly mild or moderate (CTCl or grade 2) multivesicular rash, sometimes accompanied by dry and itchy skin on the basis of erythema.

Common (>1-≤10%)

Digestive system: Metabolism and nutrition: Skin and appendages: Whole body: Ophthalmology: Vomiting, mainly mild or moderate (CTC level 1 or 2). Anorexia, mild or moderate (CTCl or 2). Oral mucositis, mostly mild (CTC grade 1). Dehydration secondary to diarrhea, nausea, vomiting, or anorexia. Abnormal liver function, mainly including asymptomatic mild or moderate elevation of transaminases (CTCl or grade 2). Nail Toxicity. Hair loss, fatigue, mostly mild (CTC grade 1), conjunctivitis and blepharitis, mostly mild (CTC grade 1).

Uncommon (>0.1-≤1%)

Hematology and Lymph: Ophthalmology: Respiratory: Increased international normal values ​​(INR) and/or bleeding events have occurred in some patients taking warfarin Corneal erosion, reversible, sometimes with abnormal eyelash growth. Interstitial lung disease is often severe (CTC 3-4) grade, and fatal cases have been reported.

Rare (>0.01-≤0.1%)

Digestive system: Pancreatitis. Very rare (<0.01%) Skin and appendages: Allergic reactions, including angioedema and urticaria, toxic epidermal necrolysis and erythema multiforme, have only been reported in individual cases * Among approximately 66,000 patients treated with gefitinib in global clinical studies and post-marketing applications (in Japan only), the overall incidence of interstitial lung disease was approximately 0.3% of patients outside Japan (including 39,000 patients) and approximately 2% in Japan (approximately 27,000 patients).

Precautions for Gefitinib

Patients receiving gefitinib occasionally develop acute interstitial lung disease, which may result in death in some patients (see "Possible Adverse Reactions" section). Mortality is increased in patients with concomitant congenital pulmonary fibrosis/interstitial pneumonia/pneumoconiosis/radiation pneumonitis/drug-induced pneumonitis. If the patient's respiratory symptoms such as shortness of breath, cough and fever worsen, treatment should be interrupted and the cause should be identified in time. When interstitial lung disease is confirmed, gefitinib should be discontinued and the patient treated accordingly. Asymptomatic elevations in hepatic transaminases have been observed (see section "Possible Adverse Reactions"). Therefore, it is recommended to check liver function regularly. It can be used with caution in patients with mild to moderate elevations of hepatic transaminases. If liver function impairment is severe, discontinuation of the drug should be considered. Substances that induce CYP3A4 activity may increase the metabolism of gefitinib and decrease its plasma concentration. Therefore, concomitant use with CYP3A4 inducers (such as phenytoin, carbamazepine, rifampicin, barbiturates or St John’s Wort) may reduce efficacy (see Drug Interactions section). Increases in International Normalized Ratio (INR) and/or bleeding events have been reported in some patients taking warfarin (see "Possible Adverse Reactions" section). Patients taking warfarin should be regularly monitored for changes in prothrombin time or INR. Drugs that cause a sustained increase in gastric pH may reduce the plasma concentration of gefitinib and thus reduce its efficacy (see the "Drug Interactions" section and the "Pharmacokinetic Properties" section). Patients should be cautioned to seek immediate medical attention if: · Any ocular symptoms · Severe or persistent diarrhoea, nausea, vomiting or anorexia. These symptoms should be managed as clinically appropriate (see "Possible Adverse Reactions" section). See also the sections "Pregnancy and Breastfeeding" and "Effects on the Ability to Drive and Use Machinery". Effect on the ability to drive and operate machines. Symptoms of fatigue may occur during treatment. These patients should be reminded when driving or operating machines.

Iressa-induced syndrome

The global average incidence of interstitial pneumonia caused by gefitinib is about 1%, and the incidence in China is even lower, only 0.5%. Fatal cases occasionally occur in Japan, but have not been reported in my country so far. We advocate that gefitinib should be used with caution in individual patients with pulmonary fibrosis, extensive radiotherapy, and severely impaired lung function to prevent the occurrence of fatal interstitial pneumonia. However, a considerable number of patients with advanced lung cancer are complicated by other lung diseases (tuberculosis, emphysema, bronchial asthma, etc.), and the lungs are prone to infection. Therefore, it cannot be completely determined that all interstitial pneumonia is caused by Iressa.

Contraindications for Iressa

Those with known severe hypersensitivity reactions to the active substance or any excipients of this product

Pharmacology and Toxicology of Iressa

Pharmacokinetic properties: Gefitinib is a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, which is usually expressed in solid tumors of epithelial origin. Inhibition of EGFR tyrosine kinase activity can hinder tumor growth, metastasis, and angiogenesis, and increase tumor cell apoptosis. In vivo, gefitinib broadly inhibits tumor growth in human tumor cell-derived lines xenografted in nude mice and enhances the antitumor activity of chemotherapy, radiotherapy, and hormonal therapy. Gefitinib has been confirmed in clinical trials to have an objective anti-tumor response and improve disease-related symptoms in locally advanced or metastatic non-small cell lung cancer. Pharmacokinetic properties After intravenous administration, gefitinib is rapidly cleared and widely distributed, with a mean elimination half-life of 48 hours.

After oral administration to cancer patients, absorption is slow, with an average terminal half-life of 41 hours. Gefitinib accumulates 2-8 times when administered once a day, and reaches steady state after 7-10 days of administration. When taking medication at 24-hour intervals, the circulating plasma drug concentration is generally maintained between 2 and 3 times. Absorption Following oral administration, peak plasma concentrations of gefitinib occur 3 to 7 hours after dosing. The average absorption bioavailability in cancer patients is 59%. Food has no significant effect on the absorption of gefitinib. In an experiment with healthy volunteers, gefitinib absorption was reduced by 47% when the pH was maintained above pH 5 (see sections 4.4 and 4.5). The mean distribution volume of gefitinib at steady state was 1400 L, indicating widespread tissue distribution. The plasma protein binding rate is nearly 90%. Gefitinib binds to serum albumin and alpha-acid glycoprotein. Metabolism in vitro study data indicate that the only P450 isoenzyme involved in the oxidative metabolism of gefitinib is CYP3A4. In vitro studies indicate that gefitinib may inhibit the CYP2D6 enzyme to a limited extent. In a clinical trial, coadministration of gefitinib with metoprolol (a CYP2D6 enzyme substrate) resulted in a small increase (35%) in the effect of this group, and its actual clinical significance has not yet been estimated.

Gefitinib did not show enzyme induction in animal experiments, and did not have a significant inhibitory effect on other cytochrome P450 enzymes (in vitro). Three biotransformation sites in the metabolism of gefitinib have been identified: metabolism of N-propylmorpholines, demethylation of the methoxy substituent on the quinazoline, and oxidative defluorination of halogenated phenyls. The major metabolite isolated in human plasma is O-desmethyl gefitinib. Its inhibitory effect on EGFR-stimulated cell growth is 14 times weaker than that of gefitinib, so it has no significant effect on the clinical activity of gefitinib. The total plasma clearance of gefitinib is approximately 500 mL/min. It is mainly excreted through feces, and about 4% is cleared through the kidneys in the form of prototypes and metabolites. Special Populations: Based on population medication data, no correlation was found between steady-state plasma concentrations and patients' age, weight, gender, race, or inosine clearance. Gefitinib was evaluated in a clinical study including 41 patients with solid tumors associated with liver metastases and normal, moderate or severe liver function impairment.

The study showed that after oral administration of gefitinib at a daily dose of 250 mg, the time to reach steady state, total plasma clearance and steady-state drug exposure levels (Cmaxss, AUC24ss) were similar in the normal liver function group and the moderately impaired group. Data obtained from 4 patients with severe hepatic impairment due to liver metastases suggest that steady-state drug exposure levels are also similar to those in patients with normal hepatic function. It has not been studied in patients with cirrhosis or hepatic impairment caused by hepatitis. Preclinical safety data relevant to prescribers of gefitinib do not indicate a genotoxic tendency. Consistent with the pharmacological activity of gefitinib, reduced fertility in mice was observed when the dose was 20 mg/kg/day. High doses (30 mg/kg/day) during the uterine period have no effect on the embryonic development of mice, but for rabbits, doses of 20 mg/kg/day and above can reduce fetal weight. No malformations were induced in either species. Doses of 20 mg/kg/day reduced pup survival in rats during pregnancy and parturition (see Pregnancy and Lactation Section). When rats were given carbon-14-labeled gefitinib orally for 14 consecutive days after delivery, the concentration of radioactivity in the milk was higher than that in the blood (see Pregnancy and Lactation section). Non-clinical (in vitro) study data indicate that gefitinib has the potential to inhibit the repolarization process of cardiac activity (such as the QT interval). Its clinical significance is unknown. Carcinogenic studies of gefitinib have not been conducted.

Mechanism of action of Iressa

(1) Compete for the Mg-ATP binding site on the EGFR-TK catalytic region and block its signal transmission;

(2) Inhibit the activation of mitogen-activated protein kinase and promote cell apoptosis;

(3) Inhibit tumor angiogenesis. Iressa was approved by the Japanese Ministry of Health and Welfare for the treatment of advanced NSCLC on July 5, 2002, and was approved by the FDA as a third-line treatment for NSCLC on May 5, 2003. Its recommended dose is 250 mg, PO, qd.

It is worth mentioning that the FDA’s decision was approved when Iressa had just completed the Phase II clinical trial and the Phase III clinical trial had not yet been completed. In 2003, the Lung Cancer Professional Committee of the Chinese Anti-Cancer Association proposed in its treatment guidelines for inoperable NSCLC: Iressa is recommended for the treatment of patients with locally advanced or distant metastatic non-small cell lung cancer who have failed platinum-based regimens and Docetaxel chemotherapy.

Clinical experience of Iressa

Gefitinib works quickly, and symptoms can be relieved after an average of 8 to 10 days of treatment. If effective, most symptoms can be seen within 1 month of medication. Rash is a common adverse reaction. You should be careful not to use alkaline chemical daily necessities, such as soap, etc. to clean the skin, just use water. When the skin is ruptured or has pustules, be careful to avoid infection and ask a dermatologist for treatment if necessary. Asymptomatic moderate transaminase elevations do not require discontinuation of medication, and some patients can recover on their own. However, if there is a moderate elevation of transaminase, it is best to stop taking the drug first and then restart the drug after recovery.

Iressa for women

There is no data on its use in pregnant or lactating women. Reproductive toxicity has been observed in animal experiments. Gefitinib and some of its metabolites have also been detected in the milk of rabbits in animal experiments (see the "Preclinical Safety Information Relevant to Prescribers" section). During treatment, women of childbearing potential are advised to avoid pregnancy and nursing mothers are advised to discontinue breastfeeding.

Iressa interaction

In vitro experiments confirmed that gefitinib is metabolized by CYP3A4. Coadministration of gefitinib with rifampicin, a known strong CYP3A4 inducer, decreased the mean AUC of gefitinib by 83% in healthy volunteers. Coadministration of gefitinib with itraconazole, a CYP3A4 inhibitor, increased the mean AUC of gefitinib by 80% in healthy volunteers. Since adverse drug reactions are related to dose and duration of action, this result may have clinical significance. Combined use with drugs that can cause gastric pH to continuously rise ≥5 can reduce the average AUC of gefitinib by 47%.

Iressa overdose

There is no specific treatment for overdose of gefitinib, and the special symptoms of overdose are not yet known. In Phase I clinical trials, a small number of patients were dosed at 1,000 mg per day. An increase in the frequency and severity of some adverse reactions was observed, mainly rash and diarrhea. Adverse reactions caused by overdose should be treated symptomatically; in particular, severe diarrhea should be given appropriate treatment.