Iressa - instructions for use, doses, side effects, contraindications

Active substanceGefitinibGefitinib

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JODAS EKSPOIM, LLC Russia

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NATIVA, LLC Russia

Iressa®

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AstraZeneca UK Ltd United Kingdom

Dosage form: & nbspfilm-coated tablets

Composition:

1 tablet, film-coated, contains:

active substance: gefitinib 250 mg;

Excipients: lactose monohydrate 163.5 mg, microcrystalline cellulose 50.0 mg, croscarmellose sodium 20.0 mg, povidone (K29-32) 10.0 mg, sodium lauryl sulfate 1.5 mg, magnesium stearate 5.0 mg;

composition of film shell: hypromellose 7.65 mg, macrogol 300 1.5 mg, iron stain red oxide E172 0.9 mg, iron oxide dye yellow E172 0.9 mg, titanium dioxide E171 0.5 mg.

Description:

Round, biconvex tablets brown, film-coated, on one side of the tablet, engraving "IRESSA"And" 250 ". On the fracture of the tablet, the nucleus is white.

Pharmacotherapeutic group:Antitumor agent - protein tyrosine kinase inhibitor

ATX: & nbsp

L.01.X.E.02 Gefitinib

Pharmacodynamics:

Gefitinib, being a selective inhibitor of epidermal growth factor receptor tyrosine kinase, the expression of which is observed in many solid tumors, inhibits tumor growth, metastasis and angiogenesis, and also accelerates apoptosis of tumor cells.

It inhibits the growth of various lines of human tumor cells and increases the antitumor activity of chemotherapeutic drugs, radiation and hormone therapy.

Clinical evidence suggests that Pressa has an objective antitumor effect, statistically significantly increases the time to progression of the disease in patients with locally advanced or metastatic non-small cell lung cancer.

It is shown that Iressa®, in comparison with docetaxel, provides a similar overall survival, more a favorable tolerability profile and superior quality of life in previously treated patients with advanced non-small cell lung cancer.

Patients who never smoked having a morphological variant of the tumor adenocarcinoma, female sex or are representatives of the Asian race, are more likely to have the effect of therapy with the drug Pressa. These clinical characteristics are also associated with a high incidence of epidermal tumor growth factor receptor mutations.

When comparing the preparation Pressa and combination carboplatin + paclitaxel in the first line of therapy for advanced non-small cell lung cancer (stage IIIB and IV) in patients of Asian race with histological form of adenocarcinoma tumors without a history of a history of the smoker (quit smoking ≥ 15 years ago and smoked ≤ 10 packs per year), Pressa® demonstrated a statistically significant survival benefit with no signs progression and objective response in comparison with the combination carboplatin + paclitaxel both in the whole group and in the group of patients in whom mutations in the epidermal growth factor receptor gene were detected. There was no statistically significant difference in overall survival between treatment groups.

Sensitivity to Gefitinib in the presence of frequent epidermal growth factor receptor mutations (fission exon 19; L858R) was convincingly confirmed by the results of clinical studies. There are separate data on the response to gefitinib in the presence of less common mutations. Sensitivity to gefitinib with rare mutations is shown G719X, L861Q and S7681, and with isolated T790M mutation or isolated exon inserts, there is resistance to gefitinib.

Circulating Tumor DNA

In the study IFUM mutations were studied in tumor tissue samples and in circulating tumor DNA samples obtained from the blood plasma of patients of the Europoid race using a test system EGFR RGQ PCR (Qiagen). Out of 1060 patients who passed the screening procedure, 652 samples of the tumor and samples of circulating tumor DNA were available for study in 652. Sensitivity (proportion of patients with a mutation at tumor tissues that showed a mutation in circulating DNA) was 65.7% (confidence interval (CI): 55.8-74.7%), the specificity (the proportion of patients with no mutation in the tumor tissue, which lacks a mutation in the circulating DNA) was 99.8% (CI: 99-100%). These data are consistent with the results of a study of circulating DNA in Asian patients in the study IPASS using a test system EGFR Mutation Test Kit (sensitivity was 43.1%, specificity was 100%). The frequency of an objective response to gefitinib therapy in patients of the European race in the study IFUM was 70%, the median survival without signs of progression was 9.7 months. These data are similar to the results obtained in patients of the Asian race in the study IPASS.

Pharmacokinetics:

After ingestion, absorption is relatively slow. The equilibrium concentration is achieved after taking 7-10 doses. Regular use of the drug once a day leads to an increase in concentration of 2-8 times compared with a single dose. The maximum concentration of the drug in the blood plasma is reached within 3-7 hours. The average absolute bioavailability in patients is 59%. Eating does not affect the bioavailability of the drug. At a pH of gastric juice above 5, the bioavailability of gefitinib is reduced by 47%.

The volume of gefitinib distribution when reaching the equilibrium concentration is 1400 liters, which indicates an extensive distribution of the drug in the tissues. The association with plasma proteins (with serum albumin and alpha1-glycoprotein) is approximately 90%.

Gefitinib undergoes oxidative "metabolism" through the cytochrome P450 cytochrome P450 isoenzyme CYP3A4.

Research in vitro showed that gefitinib slightly inhibits the enzyme CYP2D6. The administration of gefitinib together with metoprolol (a substrate for CYP2D6) resulted in a slight increase (by 35%) in the concentration of metoprolol, which is not clinically significant.

Metabolism gefitinib occurs in three ways: the metabolism of the N-propylmorpholine group, the demethylation of the methoxyl group to the quinazoline moiety, and the oxidative dephosphorylation of the halogenated phenyl group.

The main metabolite, determined in blood plasma - O-desmethylgefitinib, has 14 times less pharmacological activity than gefitinib in the cell growth ratios stimulated by the epidermal growth factor, which makes it unlikely its significant effect on the clinical activity of gefitinib.

The total plasma clearance of gefitinib is approximately 500 mL / min. The average half-life is 41 hours. The drug is excreted mainly with feces. The kidneys produce less than 4% of the administered dose.

The relationship between the lower level of the equilibrium concentration of the drug and its age, body weight, sex, ethnicity or creatinine clearance is not revealed.

Against the background of the daily administration of the Iress® preparation at a dose of 250 mg, the time to reach the equilibrium concentration, the total plasma clearance and equilibrium concentration were similar for groups of patients with normal liver function and with moderate hepatic insufficiency.Data for 4 patients with severe hepatic insufficiency due to liver metastases suggest that the equilibrium concentration in these patients is similar to that in patients with normal liver function.

Features of the action of Iress® in patients with impaired hepatic function due to cirrhosis or hepatitis are not investigated.

Indications:

Locally advanced or metastatic non-small cell lung cancer with the presence of activating mutations of the tyrosine kinase domain of the epidermal growth factor receptor in the first line of therapy.

Locally advanced or metastatic non-small cell lung cancer refractory to chemotherapy regimens containing platinum derivatives.

Contraindications:

Increased sensitivity to gefitinib or other components of the drug.

Pregnancy and lactation.

Children and adolescence (safety and efficacy in this group of patients is not assessed).

Carefully:

With idiopathic pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, post-radiation pneumonia, drug pneumonia (an increased mortality rate from these diseases was observed against the background of drug treatmentIressa®); with a weak and moderate increase in the activity of "liver" transaminases and bilirubin level.

Dosing and Administration:

Inside, 250 mg once a day, regardless of food intake.

In the event that the patient missed the next dose, the missed dose should be taken if at least 12 hours remained before the next dose was received. Do not take a double dose of the drug to compensate for the missed dose.

The tablet can also be dispersed in 100 ml of drinking (non-carbonated) water. Other liquids can not be used. For proper dissolution, it is necessary to lower the tablet into water without mashing, stir until it is completely destroyed (about 15 minutes) and immediately drink the resulting suspension. Pour another half a glass of water, rinsing the walls and drinking the resulting suspension.

A suspension of the Iress® preparation can also be administered via a nasogastric tube.

It is not necessary to correct the dose of Iress®, depending on the age of patients, body weight, ethnicity, sex, kidney function, and moderate and severe hepatic insufficiency due to metastatic liver damage.

Correction of dose: in patients with poorly stopping diarrhea against the background of treatment or adverse reactions from the skin, a short-term interruption in treatment (up to 14 days) is possible, with the subsequent resumption of treatment with the Iress® preparation at a dose of 250 mg / day.

Side effects:

The most common side effects observed in more than 20% of cases were diarrhea, skin and acne, itching, dry skin. Usually adverse reactions occur during the first month of the drug and are usually reversible. Approximately 10% of patients had serious adverse reactions (3-4 degree of severity according to the general criteria of toxicity). However, only 3% of patients had discontinued therapy due to adverse reactions.

The observed undesirable reactions are presented below.

Determination of the frequency of adverse reactions: very often (≥10%); often (≥1 - <10%); infrequently (≥0.1 - <1%); rarely (≥0.01 - <0.1%).

From the coagulation system of the blood: often - hematuria and nasal bleeding; infrequently - hypocoagulation and / or increased bleeding frequency when taking warfarin.

On the part of the digestive system: very often - diarrhea (in some cases - pronounced), nausea (mostly of a low degree of severity),vomiting (mostly of mild or moderate severity), stomatitis (mostly mild), anorexia (mild to moderate), increased ALT activity (mostly mild to moderate); often - dehydration (due to diarrhea, nausea, vomiting and anorexia), dry mouth (mostly mild), increased activity ACT (mostly mild to moderate), increased bilirubin levels (mostly mild to moderate); infrequently - pancreatitis, perforation of the digestive tract, hepatitis (reported on single cases of hepatic insufficiency, in some cases with fatal outcome).

On the part of the organs of vision: often - conjunctivitis, blepharitis, xerophthalmia (mostly of a low degree of severity); infrequently - keratitis, reversible erosion of the cornea, dysplasia of eyelash growth.

On the part of the respiratory system: often - interstitial pneumonia (3-4 degrees of toxicity, up to a lethal outcome).

From the side of the urinary system: often - an asymptomatic increase in the level of creatinine in the blood, proteinuria, cystitis; rarely - hemorrhagic cystitis.

From the skin and skin: very often - a rash (pustular), itching, dry skin, including the formation of cracks against the background of erythema; often - nail changes, alopecia; rarely - bullous skin changes, including toxic epidermal necrolysis, Stevens-Johnson syndrome and multiforme exudative erythema, cutaneous vasculitis.

Allergic reactions: infrequently - angioedema, urticaria

Other: very often - asthenia (mainly of a low degree of severity); often pyrexia.

Overdose:

Possible symptoms are an increase in the frequency and severity of some adverse reactions, mainly diarrhea and skin rash.

Treatment is symptomatic. The antidote is unknown.

Interaction:

The co-administration of gefitinib and rifampicin (a potent inducer of the isoenzyme CYP3A4) leads to a decrease in the mean "under-curve area" (AUC) for gefitinib by 83%.

The simultaneous administration of gefitinib and itraconazole (inhibitor of the isoenzyme CYP3A4) results in an increase of 80% in the AUC of gefitinib, which may be clinically significant, since the adverse events depend on dose and concentration.

Simultaneous administration of gefitinib and drugs that significantly (≥ 5) and prolonged the pH of the gastric contents, led to a 47% reduction in AUC for gefitinib.

With the combined use of gefitinib and vinorelbine, an increase in the neutropenic effect of vinorelbine is possible.

Drugs that induce the activity of the isoenzyme CYP3A4, can increase metabolism and reduce the concentration of gefitinib in the blood plasma. Thus, concomitant administration of gefitinib with inductor preparations of the CYP3A4 isoenzyme, such as phenytoin, carbamazepine, barbiturates, tincture of St. John's wort, can reduce the effectiveness of gefitinib.

Special instructions:

When deciding whether to prescribe Iress® in the first line of therapy for locally advanced or metastatic NSCLC, it is recommended that the mutation of the EGFR (epidermal growth factor receptor) mutation in tumor tissue in all patients is recommended. If a tumor tissue sample is not available for testing, circulating tumor DNA obtained from blood samples (plasma) can be used.

To determine mutations in tumor tissue samples and circulating tumor DNA, it is important that a validated and reliable technique be chosen to minimize possible false negative and false positive results.

In the first line of therapy, Iress® can not be used in place of chemotherapy in patients with no EGFR mutation.

Sometimes, patients taking the preparation of Iress®, noted interstitial lung damage, in some cases with a fatal outcome. With the increase in symptoms such as shortness of breath, cough, fever, the use of the drug should be stopped and immediately examined. If the patient is confirmed to have an interstitial lung disease, the preparation of Iress® is discontinued and the patient is treated accordingly.

The most common development of interstitial lung lesions was observed in Japan (approximately 2% of the 27,000 patients taking Iress®) compared with other countries (0.3% of the 39,000 patients).

Among the factors that increase the risk of interstitial lung injury were: smoking, severe general condition (PS> 2), normal lung tissue according to computed tomography (<50%), duration of illness (NSCLC) <6 months, interstitial pneumonia in history, (> 55 years), concomitant cardiovascular diseases.

Against the background of taking the drug Iress®, there was an asymptomatic increase in the activity of "liver" transaminases and bilirubin level, infrequently developed hepatitis. There have been reports of isolated cases of hepatic insufficiency, in some cases fatal, and it is recommended that the liver function is periodically evaluated. With a marked increase in the activity of transaminases and the level of bilirubin, the drug should be discontinued.

In clinical studies of the drug Iress®, cardiovascular complications were noted. Communication with the use of Iress® was not established.

In patients receiving warfarin, prothrombin time should be monitored on a regular basis.

When developing severe or prolonged diarrhea, nausea, vomiting, or anorexia, the patient should immediately consult a doctor.

With acute development or worsening of signs and symptoms of keratitis: inflammation of the eyes, lacrimation, photosensitivity, blurred vision, soreness and / or redness of the eyes, the patient should immediately consult an ophthalmologist. When confirming ulcerative keratitis, therapy with Iress® should be stopped.If the symptoms persist or re-develop with the resumption of Iress®, consideration should be given to the complete withdrawal of this medication.

When using Iress® in combination with radiotherapy as a first-line therapy in children with brainstem glioma or non-radically removed glioma of supratentorial location, 4 cases (one lethal) of cerebral hemorrhages were reported. Another case of cerebral hemorrhage was noted in a child with ependymoma with monotherapy with Iress®. In adults with non-small cell lung cancer, when treated with Iress®, these side effects are not documented in any case. There have been reports of cases of development of perforation of the gastrointestinal tract in patients on the background of the Iress® preparation. In most cases, this is associated with other known risk factors, such as simultaneous use of steroids, NSAIDs, a history of peptic ulcer disease, old age, smoking, the presence of metastases in the large intestine at the site of perforation.

Men and women of childbearing age during treatment with Iress® and at least 3 months after treatment should use reliable methods of contraception.

Patients with rare hereditary diseases, such as lactose intolerance, lactase deficiency or malabsorption syndrome, Iress® should be administered with caution, due to the presence of lactose in the formulation.

Effect on the ability to drive transp. cf. and fur:

Since during the treatment with Iress®, such side effects as asthenia, nausea and vomiting can develop, caution should be exercised when driving a car and engaging in other potentially dangerous activities requiring increased attention and speed of psychomotor reactions.

Form release / dosage:

Tablets, film-coated, 250 mg.

Packaging:

For 10 tablets in a blister of PVC / aluminum, 3 blisters per package of aluminum foil.

The package, together with the instruction for medical use, is placed in a cardboard box with the control of the first autopsy.

Storage conditions:

At temperatures not higher than 30 ° C, in the original packaging.

Keep out of the reach of children.

Shelf life:

4 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:П N016075 / 01

Date of registration:06.10.2009 / 10.07.2017

Expiration Date:Unlimited

The owner of the registration certificate:AstraZeneca UK LtdAstraZeneca UK Ltd United Kingdom

Manufacturer: & nbsp

ASTRAZENECA UK, Ltd. United Kingdom

Representation: & nbspAstraZeneca Pharmaceuticals Ltd.AstraZeneca Pharmaceuticals Ltd.

Information update date: & nbsp27.11.2017

Illustrated instructions

Instructions

Iressa® (Iressa®)