Irona Astra supports the treatment of lung cancer (3 blisters x 10 tablets)

Dosage form Box of 3 blisters x 10 tablets
Specifications Gefitinib

Ingredient

Composition information	Content
Gefitinib	250mg

Uses

Indications

Iressa is indicated for treatment for adult patients with non -small cell lung cancer patients in the spot or metastatic progression stage that has EGFR TK activation mutations.

Pharmacology

Therapy Pharmacology Group: Anti -cancer drug, Protein Kinase inhibitors, ATC code: L0l: L0E02.

Mechanism of impact and effect

Epidermal Growth Factor (EGF) and receptor (EGFR (Her1 ERBB1]) plays a major role in the development and proliferation of normal cells and cancer cells. EGFR activity in cancer cells is an important factor in tumor growth, compartment of dead cells, increasing new blood vessels and promoting new bloodstreams and promoting new metastatic blood processes tumor.

Gefitinib is a small molecular active ingredient, selectively inhibits Tyrosin Kinase on receptors of epidermal development and effective treatment in patients with active tumors of EGFR Tyrosin Kinase regardless of treatment. There is no clinical effect related to patients with tumors without EGFR mutations.

Common EGFR activation mutations (lost on Exon 19, L858R) have a lot of data that responds to Gefitinib sensitivity; For example: The survival time does not progress to HR (95% Cl) 0.489 (0.336; 0.710) in the gefitinib group compared to the double chemotherapy group [wjtog3405]. Few data responded to gefitinib more in patients with rare mutations, available data show that G719X, L861Q and S7681 are drug sensitive mutations; And T790M alone or mutant to insert paragraphs at Exon 20 is a drug resistance mechanism.

DNA of tumors in the circulatory system (CTDNA)

In iFum clinical research, mutations are evaluated on the tumor sample and the CTDNA sample extracted from plasma, using the Therascreen EGFR RGQ PCR test set (Qiagen). Both CTDNA and tumor samples can evaluate 652 patients out of 1060 patients screening. The objective response ratio of a group of patients with positive mutant tests in both tumor and CTDNA samples is 77% (95% CI: 66% -86%), and in the patient group, there is only a positive mutation on the tumor sample of 60% (95% CI: 44% - 74%).

Pharmacokinetics

absorption

After taking Gefitinib, the absorption is relatively slow and the concentration of Gefitinib peaks in plasma reaches 3-7 hours after taking the drug. Absolute bioavailability is 59% in cancer patients. The food does not significantly change the gefitinib level in the body. In a healthy volunteer test with a maintenance pH of> 5, the gefitinib concentration in the body decreased by 47%, may be due to reduced solubility of gefitinib in the stomach (see "warning" and "interaction").

Distribution: Gefitinib's average distribution volume in the constant state is 1400 liters, proving to be widely distributed into tissues. About 90% of the drug is connected to plasma proteins. Gefitinib is connected to albumin and α1-acid glycoprotein in serum.

In vitro data shows that Gefitinib is the substrate for the transportation through the cell membrane of PGP protein.

Metabolism

In vitro data shows that CYP3A4 and Cyd2D6 are the main IZYM P450 related to Gefitinib's oxidative metabolism.

In vitro studies have proved that Gefitinib is less likely to inhibit CYP2D6. Gefitinib shows no enzyme induction in animal studies and does not significantly inhibit (in vitro) on any cytochrom P450 enzyme.

Gefitinib is widely metabolized in humans. 5 metabolites have been fully identified in feces and 8 metabolites in human plasma. The main metabolites are identified as O-Desmethyl Gefitinib, 14 times poorly active than Gefitinib about the ability to inhibit cell growth activated by EGFR and no inhibiting tumor cell growth in mice. Therefore, this metabolic is considered not to contribute to the clinical impact of Gefitinib.

In vitro, O-Desmethyl Gefitinib have been shown to be produced through CYP2D6 enzymes. The role of CYP2D6 enzyme in the process of clearing Gefitinib metabolism has been evaluated in a clinical study on healthy volunteers who surveyed genotypes of CYP2D6 (genotyped for CYP2D6 status). In poor metabolic people, the O-Desmethyl Gefitinib is not detected to be produced at a measurable level. The concentration and time of contact with Gefitinib in the blood in both the strong metabolic group and the poor metabolic group both wide and coincide with each other but the average concentration and time of contact with Gefitinib in the blood in the blood group in poor metabolic groups are twice as high as. The phenomenon of non -CYP2D6 people with higher medical contacts and duration of blood in the blood may have clinical significance because they have encountered adverse reactions related to the dose and drug concentration in the body.

Elimination

Gefitinib is excreted mainly in the form of metabolites through fertilizer, drug excretion and metabolic substances through the kidneys less than 4% of the dose.

The total gefitinib clearance in plasma is about 500 ml/minute and the average of the last half -life is 41 hours in cancer patients. Drinking Gefitinib once a day will lead to accumulation of drugs from 2 to 8 times, with concentration and contact time in a stable state achieved after 7-10 doses. In a stable state, the concentration of drug in circulatory plasma is maintained 2-3 times with a 24 -hour dose.

Special population groups: When analyzing data based on the population group in cancer patients, there is no determination of the relationship between the bottom concentration in the predicted stable state (Predicted Steady State Trough Concentration) and patient age, gravity, gender, race or creatinine waste (> 20 ml/minute).

Hepatic failure

In a phase-open label study, Gefitinib 250 mg is used in patients with severe, medium or mild hepatic failure due to cirrhosis (according to Child-Pugh classification), there has been an increase in blood concentration in all groups compared to healthy evidence. It has recorded the exposure level with Gefitinib increased by 3.1 times the average and severe liver failure patients. No patients with cancer, all have cirrhosis and some people have hepatitis. This exposure increase is clinically significant because it has encountered adverse reactions related to the dose and exposure to the body.

Gefitinib has been evaluated in a clinical trial that carries out over 41 patients with solid tumors (solid tumor) and normal liver function, medium or severe liver function (classification of toxic toxic assessments is common based on AST, alkalin phosphatase and bilirubin) due to liver metastasis. The results showed that after daily dose of IRESSA 250 mg, the values such as the time to achieve stable concentration in the blood, the total plasma clearance and the contact level in a stable state (CMAXSS, AUC24SS) similar in groups with normal liver function and liver function impaired average level. Data of 4 patients with severe liver function due to liver metastasis shows that the exposure level in the stable state of these patients is similar to that in patients with normal liver function.

Before taking Irona Astra supports the treatment of lung cancer (3 blisters x 10 tablets)

How to use

can take medicine during or outside meals, at the same time of the day.

The drug can be swallowed with a little water or in case of unable to take the whole pill, it can be dispersed in the water. Dropage should be dropped in half a glass of drinking water (no carbonate). Do not use with other drinks.

Do not crush the pill, drop the pills in half a glass of water. Stir until the pill is completely dispersed (about 20 minutes) and take the drug immediately after the drug is completely dispersed (that is, within 60 minutes). Coated with half a glass of water and drink. The dispersed drug can also be used through a thick nasal catheter or a gastric catheter.

Dosage

treatment with Irona should be conducted and monitored by doctors who have experience in cancer treatment.

Iressa recommended dose is 1 tablet 250 mg, once a day. If you forget to take 1 dose of the drug, you should drink as soon as you remember. If you forget to take the medicine for less than 12 hours until the time of taking the next dose, the patient should not use the dose that has forgotten to drink. Patients should not use double doses (take 2 dose at the same time) to compensate for the dose for forgotten to drink.

Children

The safety and effectiveness of IRESSA in children and teenagers under the age of 18 have not been established. No Gefitinib has not been used in children with non -small cell lung cancer.

Hepatic failure

Patients with average to severe liver failure (Child Pugh B or C) due to cirrhosis have increased gefitinib levels in plasma. It is advisable to closely monitor the adverse reactions in these patients. Non -increasing plasma concentrations in patients with increased aspartat transaminase (AST), alkalin phosphatase or bilirubin due to liver metastasis.

kidney failure

No dose adjustment in patients with impaired renal function has creatinine clearance> 20 ml/min. There are very few data in patients with creatinine clearance ≤20 ml/min and need to be cautious when using the drug in this patient group.

Elderly patients

No need to adjust the dose based on the age of the patient.

Patients with enzyme impaired CYP2D6: There is no recommendation to adjust the specific dose in patients with genotype metabolized through CYP2D6 decreases, but in these patients should be closely monitored for adverse reactions.

Adjust the dose when the toxicity of the drug: Patients with diarrhea or adverse reactions on the skin without tolerance can be successfully controlled when stopped taking the drug for a short time (≤14 days) and then re -use the dose of 250 mg. For patients who cannot tolerate drugs after a round of treatment, Gefitinib should be discontinued and consider alternative treatments.

Note: The above dose is for reference only. Specific dosage depends on the condition and level of progression of the disease. For a suitable dose, you need to consult a doctor or medical specialist.What to do when overdose? However, in phase clinical research, a few patients were treated with a dose of up to 1000 mg/day. The frequency increase and severity of some adultery reactions, mainly diarrhea and skin rash.

Adultery reactions due to overdose should be treated with symptoms; Especially severe diarrhea should be treated as clinically indicated. In a study with a limited number of patients treated weekly at a dose of 1500 mg to 3500 mg. In this study, the concentration and time of exposure to Irona did not increase with the dose, the adverse reactions were mainly mild to moderate and in accordance with the knowing IRESSA drug safety data.

In an emergency, call the 115 emergency center immediately or go to the nearest local health station.

What to do when you forget 1 dose? However, if the time to relax with the next dose is too short, skip the dose and continue the calendar of the drug. Do not use double dose to compensate for missed dose.

Side Effects

Summary of drug safety data

Gross data from phase clinical trials III such as Isel, Interest and IPASS (performing on 2462 patients treated with IRESSA), the most common adverse adverse reactions (ADR) are recorded on> 20% of patients with diarrhea and skin reaction (including rash, acne, dry and itchy skin). Adultery reactions due to drugs often appear in the first month of treatment and generally can stop on their own. About 8% of patients have serious adverse reactions (levels 3 and 4 according to the common toxic assessment criteria - CTC: Common Toxicity Criteria). However, only 3% of patients must stop treatment due to adverse reactions.

Interstitial lung disease (ILD) occurs in 1.3% of patients, often suffering from severity (level 3-4 according to common toxic assessment criteria). There is also the result of death.

Adultery reaction classification table

Drug safety data presented in Table 7 is based on Gefitinib's clinical development programs. Adultery reactions are arranged in frequency columns in Table 7 if it can be based on the percentage of adverse reaction reports that can be compared in gross data from phase III clinical trials such as Isel, Interest and IPASS (over 2462 patients treated with IRESSA).

The frequency of adultery reactions is determined as follows: Very common (≥1/10); Common (> 1/100 to

In each classification group, adverse reactions are arranged in the order of gradual decrease.

Disorders of metabolism and nutrition:

Very common: Anorexia has a light or medium nature (CTC level 1 or 2).

Eye disorders:

Common: conjunctivitis, iris and dry eyes*, mainly with a mild nature (CTC level 1).

Common: Bleeding, such as nosebleeds and blood.

Common: interstitial lung disease (1.3%), usually serious (CTC level 3 - 4). There have been reports on life -threatening consequences.

Very common:

Diarrhea is mainly light or medium nature (CTC level 1 or 2). 1).

Very common: Increasing alanin aminotransferase is mainly mild to moderate. Liver ***.

Very common: The skin reaction is mainly mild or moderate pustules (CTC level 1 or 2), sometimes tilted with dry skin, including chapped on the red rash. jute.

Common:

Increasing blood creatinine.

proteinuria.

Very common: Main weakness (CTC degree 1).

Common: Fever.

* This event can occur in combination with other dry conditions (mainly reactions on the skin) recorded to Iressa.

** The frequency of the entire adverse reaction on allergic reactions recorded in the analysis of the testing of Isel, Interest and IPASS tests is 1.5% (36 patients). 14 out of 36 patients were excluded from the frequency of the report because there was no cause of allergies or the allergic reaction was the result of using another pharmaceutical.

*** consists of several individually liver failure reports that some cases lead to death.

Interstitial lung disease (ILD)

In Interest clinical research, the proportion of adverse reactions is 1.4% (10) patients in the Gefitinib group compared to 1.1% (8) patients in the Docetaxel group. An adulterous adultery reaction is dead and occurs in a patient in the Gefitinib group.

In Isl clinical research, the frequency of ILD type events in all patients is similar and about 1% in both treatment branches. The majority of ILD events recorded that in Asian racial patients and the frequency of ILD between Asian patients treated with Iressa and the placebo group is about 3 % and 4 % in the corresponding appropriate. There is 1 patient in the placebo group with an ILD death.

In a monitoring study after bringing the drug to the market in Japan (3350 patients), the rate of ILD type events recorded in patients using Gefitinib is 5.8%. The ratio of the ILD adverse adverse reaction is 38.6%.

In the clinical trial of Pha III label (IPASS) on 1217 patients comparing Ireessa with chemotherapy for 2 carboplatin/paclitaxel drugs as initial treatment in non -small -cell lung cancer patients in Asia, the rate of ILD type is 2.6% in the treatment group with IRESSA compared to 1.4% in the treatment group with carbooplate/paclitaxel.

Notify the doctor with unwanted effects when using the drug.

Warnings

Before using the drug you need to read the instructions carefully and refer to the information below.

contraindicated

Irona drugs contraindicated in the following cases:

Hypersensitivity to active ingredients or excipients.

Women who are breastfeeding.

Be cautious when using

When considering the use of IRESSA to treat patients with non -small cell lung cancer patients on the progressive or metastatic stage, the EGFR mutation assessment is recommended for tumor tissue for all patients. If the tumor sample cannot be evaluated, the DNA sample of the tumor can be used in the circulatory system (CTDNA) collected from the blood sample (plasma). Only use test methods with repetition, reliability, sensitivity and utilities have been proven to determine the mutant of the tumor EGFR or CTDNA to avoid false negative or fake negative results.

Interstitial lung disease (ILD)

Interstitative lung disease, which can be acute, have been observed in 1.3% of patients taking Gefitinib, and some cases may die. If the patient has a deterioration with respiratory symptoms such as shortness of breath, cough and fever, IRESSA should be stopped and checked immediately. If diagnostic confirmation is interstitial lung disease, IRESSA should be discontinued and treated patients with appropriate measures.

In a physical and physical pharmacological study with control at the exemplary conducted on 3159 patients with non -small cell lung cancer (NSCLC) were monitored for 12 weeks when taking Gefitinib or chemotherapy, the risk factors for interstitial lung development (ILD) as follows have been identified (regardless of the patient using irona or chemotherapy): Smoking, poor pulmonary condition (PS ≥2) Just take the CT layer (≤ 50%), newly diagnosed with NSCLC (

Liver poisoning and liver function impairment

Abnormalities of liver function tests (including hyperlemen aminotransferase, Aspartat aminotransferase, bilirubin) have been recorded but rarely shows hepatitis. Some individually reported liver function that some cases lead to death. Therefore, patients are recommended to check the liver function periodically. Gefitinib should be used carefully in patients who change liver function at a mild or medium level. Consider stopping using the drug if the changes are serious.

impaired liver function caused by cirrhosis has been recognized as an increase in gefitinib concentration in plasma.

Interaction with other drugs

The induction substances with the CYP3A4 enzyme system may increase gefitinib metabolism and reduce gefitinib levels in plasma. Therefore, when combined with CYP3A4 induction substances (such as Phenytoin, Carbamazepin, Rifampicin, Barbiturat or pharmaceutical preparations containing St John’s World/Hypericum Perforatum) can reduce the effectiveness of the drug and thus avoid using these drugs.

In patients with metabolic genotypes through CYP2D6 decreasing, strong CYP3A4 inhibitors can lead to increased gefitinib concentration in plasma. When starting with CYP3A4 inhibitors, patients need to be closely monitored by Gefitinib's adverse reactions.

Inr (International Normalise Ratio) and/or hemorrhagic events have been reported in some patients using warfarin. Should regularly monitor changes in prothrombin (PT) or INR time in patients using warfarin.

The drugs significantly increase and extend the gastric pH level such as proton pump inhibitors and H2 receptor resistant drugs that can reduce bioavailability and gefitinib concentration in plasma and thus reduces the effectiveness of the drug. Anti -acid drugs if used regularly near the time of taking Gefitinib may have the same effect.

Data from phase clinical studies II, when used simultaneously Gefitinib and Vinorelbin shows that Gefitinib may increase Vinorelbin's neutropenia impact.

lactose: Iressa contains lactose. Patients with rare genetic problems with galactose tolerance, Lapp Lactose deficiency or malposive glucose-galactose should not take this drug.

Other cautions

advise patients to see a doctor immediately when diarrhea is serious or persistent, nausea, vomiting or anorexia that can indirectly lead to body dehydration. These symptoms can be treated according to clinical illness.

Patients with signs and symptoms of keratitis such as acute or more severe condition: eye inflammation, gland, sensitivity to light, blurred vision, eye pain and/or red eye should quickly consult an eye specialist.

If diagnosed has been identified as corneal ulcer, it is advisable to stop treating with gefitinib and if the symptoms are not completely or recurrent when using Gefitinib, consider stopping the long -term use of Gefitinib.

In a phase study I/II used gefitinib and radiation therapy in newly diagnosed brain stem glaus nerve tumors (brain stem gloma) or malignant nerve tumors on the tent have been removed (Incompletely Resected Supratentorial Malign Gloma), there are 4 cases of hemorrhage in the central nervous system (including 1 death case) research participating in the research. A case of hemorrhage in the central nervous system in children with ventricular meninges (Ependymoma) is also recorded in the mere Gefitinib test. Increasing the risk of cerebral hemorrhage in adult patients with non -small cell lung cancer using Irona has not been established.

There has been a record of gastric gastric perforation in patients using Gefitinib. In most cases, this is related to other known risk factors, including high age, simultaneous use of other drugs such as steroids, NSAID anti -inflammatory, gastric ulcerative disease, smoking or metastasis at the puncture position.

The effect of the drug on the ability to drive and operate machinery

has reported on symptoms of depression during treatment with Gefitinib. Therefore, patients with this symptom should be cautious when driving or operating the machine.

Use drugs for women during pregnancy and lactation

Women of reproductive age:

Recommended women of reproductive age should not be pregnant during treatment with this drug.

Pregnancy:

There is no data on gefitinib for pregnant women. Animal studies have shown that drugs are toxic to the reproductive system. It is unknown the risk of humans. Iressa should not be used during pregnancy unless it is really necessary.

breastfeeding period:

It is still not known whether Gefitinib will excrete in human milk. Gefitinib and gefitinib metabolites enter the milk mouse milk. Contraindicated to use gefitinib while breastfeeding and so women who are breastfeeding must stop breastfeeding during IRESSA treatment.

Drug interaction

gefitinib metabolizes through Cytochrom P450, mainly isoenzyme CYP3A4 and through CYP2D6.

Drugs can increase the level of gefitinib in the blood

In-Vitro studies show that Gefitinib is a substrate of glycoprotein. The current data does not indicate any clinical links with this in-shitro discovery.

CYP3A4 inhibitors can reduce the clearance of Gefitinib. Simultaneously used with strong inhibitors of CYP3A4 (such as Ketoconazole, Posaconazole, Voriconazole, Enzyme inhibitors, Clarithromycin, Telithromycin) can increase the gefitinib level in plasma. This increase may be clinically significant for acknowledging the adverse reactions related to the dose and drug concentration in the body.

This increase may be higher in the individual patient with a metabolic genotype through CYP2D6. Pre -treatment with iTraconazole (a strong CYP3A4 inhibitor) has increased 80% of the average AUC value of Gefitinib in healthy volunteers. If simultaneously used with CYP3A4 inhibitors, it is advisable to closely monitor the adverse reactions of Gefitinib.

There is no data on simultaneous treatment with CYP2D6 inhibitors, but these enzyme strong inhibitors may increase the level of gefitinib in plasma about twice in patients with strong metabolism through CYP2D6. If used simultaneously with strong CYP2D6 inhibitors, it is advisable to closely monitor the adverse reactions on patients.

Medications that reduce Gefitinib concentration in plasma

CYP3A4 induction drugs may increase metabolism and reduce gefitinib levels in plasma and thus reduce the effectiveness of Gefitinib. Should avoid simultaneous use with CYP3A4 induction drugs (such as Phenytoin, Carbamazepin, Rifampicin, Barbiturate or St John’s Wort (Hypericum Perforatum)). Pre -treatment with rifampicin (strong CYP3A4 induction drug) in healthy volunteers reduces about 83% of the average AUC value (see the "warning" section).

Significant increase in gastric pH levels may reduce the level of gefitinib in plasma and thus reduce the effectiveness of Gefitinib. High doses of short -action antacids may have the same effect if used regularly at the time of gefitinib. Simultaneous use of gefitinib with ranitidin at a dose level increases gastric pH ≥5, leading to a decrease of about 47% of the average AUC value in healthy volunteers.

Medications are changed in plasma concentrations due to the influence of gefitinib

In-Vitro studies show that Gefitinib is less likely to inhibit CYP2D6. In a clinical trial, Gefitinib is simultaneously used with Metoprolol (a substrate of CYP2D6). This increases 35% of concentration and time of contact with Metoprolol. This increase is meaningful to CYP2D6 substrates with narrow treatment index. Consider when using CYP2D6 substrates in combination with Gefitinib, the dose adjustment of CYP2D6 substrate, especially drugs with narrow therapeutic windows.

Gefitinib inhibits BCRP in-Vitro transport protein, but it is still unclear clinically related relationships with this finding.

Other interactive capabilities: Inranged and/or hemorrhagic events have been reported in some patients using warfarin.

Storage

Do not store more than 30 ° C, store in the original packaging.

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