Iressa

General characteristics. Structure:

1 tablet, film coated, contains:
active agent: гефитиниб 250 mg
excipients: lactoses monohydrate of 163,5 mg, cellulose of microcrystallic 50,0 mg, croscarmellose sodium of 20,0 mg, povidone (K29-32) of 10,0 mg, sodium lauryl sulfate of 1,5 mg, magnesium stearate of 5,0 mg;
structure of a film cover: gipromelloza of 7,65 mg, macrogoal of 300 1,5 mg, dye ferrous oxide of red E172 0,9 mg, dye ferrous oxide of yellow E172 0,9 mg, titanium mg E171 0,5 dioxide.
Description
Round, biconvex tablets of brown color, film coated, on one party of a tablet an engraving of "IRESSA" and "250". On a tablet break a kernel of white color. 

Pharmacological properties:

Pharmacodynamics. Гефитиниб, being the selection inhibitor of a tyrosinekinase of receptors of an epidermal growth factor which expression is observed in many solid tumors, slows down growth of a tumor, innidiation and an angiogenesis, and
also accelerates apoptosis of tumor cells.
Slows down growth of various lines of tumor cells of the person and increases antineoplastic activity of chemotherapeutic drugs, radiation and hormonal therapy.
Clinical data demonstrate that Iressa® possesses objective antineoplastic action, statistically authentically increases time before progressing of a disease at patients with local widespread or metastatic not small-celled cancer of a lung.
It is shown that Iressa®, in comparison with dotsetaksely, provides similar general survival, more favorable profile of portability and the surpassing quality of life at earlier treated patients with widespread not small-celled cancer of a lung.
The patients who never were smoking, having morphological option of a tumor an adenocarcinoma, a female or being representatives of Asian race will have effect of therapy by the drug Iressa® more possibly. These
clinical characteristics are also associated with high frequency mutations of a receptor of an epidermal growth factor of a tumor.
When comparing the drug Iressa® and a combination карбоплатин + paklitakset in the first line of therapy of widespread not small-celled cancer of lung (a stage of IIIB and IV) at patients of Asian race with a histologic form of a tumor the adenocarcinoma with not burdened anamnesis of the smoker (10 packs which left off smoking ≥ 15 years ago and smoking ≤ a year), showed to Iressa® statistically significant advantages in survival without signs
and the objective answer in comparison with a combination карбоплатин + paklitakset progressing, both in all group, and in group of patients at whom mutations of a gene of a receptor of an epidermal growth factor were revealed.
Statistically significant distinction in the general survival between groups of treatment is noted.

Pharmacokinetics. After intake, absorption happens rather slowly.
Equilibrium concentration is reached after reception of 7-10 doses. Regular purpose of drug leads to increase in concentration by 2-8 times in comparison with a single dose once a day. The maximum concentration of drug in a blood plasma is reached within 3–7 hours. Average values of absolute bioavailability at patients make 59%. Meal does not influence bioavailability of drug. At an indicator рН a gastric juice above the 5th bioavailability of a gefitinib decreases by 47%.
The volume of distribution of a gefitinib at achievement of equilibrium concentration makes 1400 l that demonstrates extensive distribution of drug in fabrics. Communication with proteins of plasma (with a seralbumin and an alpha 1 glycoprotein) makes about 90%.
Гефитиниб is exposed to oxidizing metabolism by means of an isoenzyme of CYP3A4 of system of P450 cytochrome.
The researches in vitro showed what гефитиниб slightly inhibits CYP2D6 enzyme. Purpose of a gefitinib together with metoprololy (substrate for CYP2D6) led to slight increase (for 35%) concentration of a metoprolol that is not clinically significant.
Metabolism of a gefitinib happens in three ways: metabolism of N-propilmorfolinovoy of group, demethylation of methoxy group on a hinazolinovy part and oxidizing dephosphorylation of the halogenated phenylic group.
The main metabolite defined in a blood plasma – O-desmetilgefitinib, has by 14 times smaller pharmacological activity in comparison with gefitiniby concerning cellular growth, stimulated an epidermal growth factor that does improbable its significant effect on clinical activity of a gefitinib.
The general plasma clearance of a gefitinib - about 500 ml/min. The average elimination half-life makes 41 hour. Drug is removed generally with excrements. Kidneys remove less than 4% of the entered dose.
Communication between the lower level of equilibrium concentration of drug and age, body weight, a floor, an ethnic origin or clearance of creatinine is not revealed.
Against the background of daily administration of drug of Iressa® in a dose of 250 mg, time of achievement of equilibrium concentration, the general plasma clearance and equilibrium concentration were similar for groups of patients to normal function of a liver and to a moderate liver failure. Data on 4 patients with a heavy liver failure owing to metastasises in a liver allow to assume that equilibrium concentration at these patients is similar to that at patients with normal function of a liver.
Features of effect of the drug Iressa® at patients with abnormal liver functions owing to cirrhosis or hepatitis are not investigated.

Indications to use:

Locally-spread or metastatic not small-celled cancer of a lung with existence of the activating mutations of the tirozinkinazny domain of a receptor of an epidermal growth factor in the first line of therapy.
Locally-spread or metastatic not small-celled cancer of a lung, refractory to the chemotherapy modes containing derivative platinum.

Route of administration and doses:

Inside on 250 mg of 1 times a day regardless of meal. If the patient missed reception of the next dose, the passed dose should be accepted if before reception of the following dose there were not less than 12 hours. It is not necessary to accept a double dose of drug for compensation of the passed dose.
The tablet can be also dispersed in 100 ml of drinking (not gassy) water. Other liquids cannot be used. For the correct dissolution it is necessary to lower a tablet in water, without kneading, to stir slowly before final fracture (about 15 minutes) and right there to drink the received suspension.
To pour a half more of a glass of water, rinsing walls and to drink the received suspension. It is also possible to appoint suspension of the drug Iressa® via the nazo-gastralny probe.
Dose adjustment of the drug Iressa® depending on age of patients, body weight, ethnic and a sex is not required, to function of kidneys, and also at the moderate and heavy liver failure caused by metastatic damage of a liver.
Dose adjustment: at patients with badly stopped diarrhea against the background of treatment or side reactions from integuments the short-term break in treatment (up to 14 days), with the subsequent resuming of treatment by the drug Iressa® in a dose of 250 mg/days is possible.

Features of use:

At the solution of a question of purpose of the drug Iressa® in the first line of therapy of locally-spread or metastatic NMRL definition of a mutation of EGFR (a receptor of an epidermal growth factor) in tumoral fabric at all patients is recommended. For definition of mutations important that the validirovanny and reliable technique allowing to minimize possible both false-negative, and false positive results was chosen. In the first line of therapy Iressa® it cannot be applied instead of chemotherapy at patients with lack of a mutation of EGFR.
Sometimes at the patients accepting the drug Iressa® intersticial damage of lungs, in certain cases with a lethal outcome was noted. At increase of such symptoms as short wind, cough, fever use of drug examination has to be stopped and immediately conducted. If at the patient existence of an intersticial pulmonary disease is confirmed, administration of drug of Iressa® is stopped and to the patient the corresponding treatment is appointed.
Most often development of intersticial damages of lungs was observed in Japan (approximately in 2% of cases at 27000 patients accepting the drug Iressa®) in comparison with other countries (in 0,3% of cases among 39000 patients).
Among the factors increasing risk of development of intersticial damage of lungs were noted: smoking, a serious general condition (PS> 2), normal pulmonary fabric according to a computer tomography <50%, duration of a disease (NMRL) <6 months, intersticial pneumonia in the anamnesis, advanced age (> 55 years), the accompanying cardiovascular diseases.
Against the background of administration of drug of Iressa® asymptomatic increase in activity of "hepatic" transaminases and level of bilirubin was noted, hepatitis infrequently developed. It was reported about isolated cases of development of a liver failure, in certain cases with a lethal outcome. In this connection it is recommended to estimate hepatic function periodically. At the expressed increase in activity of transaminases and level of bilirubin administration of drug has to be stopped.
In clinical trials of the drug Iressa® cardiovascular complications were noted. Connection with administration of drug of Iressa® was not established.
At the patients accepting warfarin it is necessary to control a prothrombin time regularly.
At development of heavy or long diarrhea, nausea, vomiting or anorexia the patient has to see a doctor immediately.
At acute development or deterioration in signs and symptoms of a keratitis: inflammations of eyes, dacryagogues, photosensitivities, illegibilities of sight, morbidity and/or reddening of eyes, the patient has to address the ophthalmologist immediately. At confirmation of an ulcer keratitis therapy by the drug Iressa® should be suspended. If symptoms do not disappear or repeatedly develop when resuming administration of drug of Iressa®, it is necessary to consider the possibility of full cancellation of this therapy.
At use of the drug Iressa® in a combination with radiation therapy as therapy of the first line at children with a glioma of a brainstem or not considerably remote glioma of supratentorial localization it was reported about 4 cases (one lethal) of hemorrhages in a brain. One more case of hemorrhage in a brain is noted at the child with an ependymoma at monotherapy by the drug Iressa®. At adult patients with not small-celled cancer of a lung at treatment by the drug Iressa® similar by-effects are not recorded in one case.
It was reported about cases of development of perforation of bodies of a GIT in patients against the background of administration of drug of Iressa®. In most cases it is connected with other known risk factors, such as a concomitant use of steroids, non-steroidal anti-inflammatory drugs (NPVP), a peptic ulcer in the anamnesis, advanced age, smoking, existence of metastasises in a large intestine in the place of perforation.
Men and women of childbearing age during treatment by the drug Iressa® and, at least, within 3 months after treatment should use reliable methods of contraception.
Patients with rare hereditary diseases, such as a lactose intolerance, deficit of lactase or a sprue should appoint the drug Iressa® with care, in connection with existence in composition of lactose.
Influence on ability to drive the car and other mechanisms
As during performing therapy by the drug Iressa® such side effects as an adynamy, nausea and vomiting can develop, it is necessary to be careful during the driving of the car and occupations other potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions.

Side effects:

The most widespread side effects observed more than in 20% of cases were diarrhea, skin and acne rash, an itch, a xeroderma.
Usually adverse reactions are shown within the first month of use of drug and are, as a rule, reversible. Approximately at 10% of patients serious undesirable reactions were noted (3-4 severity according to the general criteria of toxicity).
However only at 3% of patients therapy was stopped owing to side reactions.
The observed undesirable reactions are given below.
Determination of frequency of side reactions: very often (≥10%); often (≥1 - <10%); infrequently (≥0,1 - <1%); seldom (≥0,01 - <0,1%).
From coagulant system of blood:  a hamaturia and nasal bleeding is frequent; infrequently  hypocoagulation and/or increase in frequency of bleedings against the background of warfarin reception.
From digestive organs: very often – diarrhea (in some cases – expressed), nausea (generally weak degree of manifestation), vomiting (generally weak or moderate degree of manifestation), stomatitis (generally weak degree of manifestation), anorexia (weak or moderate degree of manifestation), increase in activity of ALT (generally weak or moderate degree of manifestation); often – dehydration (owing to diarrhea, nausea, vomiting and anorexia), dryness in a mouth (generally weak degree of manifestation), increase in activity of nuclear heating plant (generally weak or moderate degree of manifestation), increase in level of bilirubin (generally weak or moderate degree of manifestation); infrequently – pancreatitis, perforation of bodies of a GIT, hepatitis (it was reported about isolated cases of development of a liver failure, in certain cases with a lethal outcome).
From organs of sight: often – conjunctivitis, a blepharitis, a xerophthalmia (generally weak degree of manifestation); infrequently – a keratitis, a reversible erosion of a cornea, a growth disorder of eyelashes.
From a respiratory organs: often – intersticial pneumonia (3-4 degrees of toxicity, up to a lethal outcome).
From an urinary system: often – asymptomatic increase in level of creatinine in blood, a proteinuria, cystitis; seldom – hemorrhagic cystitis.
From skin and integuments: very often – rash (pustular), an itch, a xeroderma, including formation of cracks against the background of an erythema; often – changes of nails, an alopecia; seldom – violent changes of skin, including a toxic epidermal necrolysis, Stephens-Johnson's syndrome and a multiformny exudative erythema, a skin vasculitis.
Allergic reactions: infrequently – a Quincke's disease, a small tortoiseshell
Others: very often – an adynamy (preferential weak degree of manifestation), it is frequent – a pyrexia.

Interaction with other medicines:

Joint purpose of a gefitinib and rifampicin (the powerful inductor of an isoenzyme CYP3A4) leads to reduction of average values "the areas under a curve" (AUC) for a gefitinib for 83%.
Co-administration of a gefitinib and itrakonazol (CYP3A4 isoenzyme inhibitor) leads to increase by 80% of AUC of a gefitinib that can be clinically significant as the undesirable phenomena depend on a dose and concentration.
Co-administration of a gefitinib and the drugs promoting considerable (≥ 5) and to long increase рН gastric contents, led to reduction of AUC for a gefitinib for 47%.
At combined use of a gefitinib and vinorelbin strengthening of neytropenichesky action of a vinorelbin is possible.
The medicines inducing activity of an isoenzyme of CYP3A4 can increase metabolism and reduce concentration of a gefitinib in a blood plasma. Thus, co-administration of a gefitinib with drugs, CYP3A4 isoenzyme inductors, such as Phenytoinum, carbamazepine, barbiturates, tincture of a St. John's Wort can reduce efficiency of a gefitinib.

Contraindications:

Hypersensitivity to a gefitinib or other components of drug.
Pregnancy and period of a lactation.
Children's and teenage age (safety and efficiency at this group of patients is not estimated).
With care: at an idiopathic pneumosclerosis, intersticial pneumonia, a pneumoconiosis, post-beam pneumonia, medicinal pneumonia (the increased mortality rate from these diseases against the background of treatment is noted by the drug Iressa®); at weak and moderate increase in activity of "hepatic" transaminases and level of bilirubin.

Overdose:

Possible symptoms – increase in frequency and weight of some side reactions, mainly, diarrhea and skin rash. Symptomatic treatment. The antidote is not known.

Storage conditions:

At a temperature not above 30 °C in original packaging. To store in the places unavailable to children. Period of validity 4 years. Not to apply after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Tablets, film coated on 250 mg. On 10 tablets in the blister from PVC/aluminium, on 3 blisters in a package from aluminum foil. The package together with the instruction on a medical use is placed in a cardboard pack with control of the first opening.