Gefitinib-native (Gefitinib-nativ)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceGefitinibGefitinib
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  • Gefitinib
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    JODAS EKSPOIM, LLC     Russia
  • Gefitinib-native
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    NATIVA, LLC     Russia
  • Iressa®
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    AstraZeneca UK Ltd     United Kingdom
    • Dosage form: & nbspfilm-coated tablets
    Composition:

    Composition per one tablet:

    Active substance:

    Gefitinib 250.0 mg

    Excipients:

    Lactose monohydrate 163.5 mg

    Microcrystalline cellulose 50.0 mg

    Croscarmellose sodium 20.0 mg

    Povidone K 30 10.0 mg

    Sodium lauryl sulfate 1.5 mg

    Magnesium stearate 5.0 mg

    Composition of the film shell

    Fallen purple 12.0 mg (hypromellose - 62.50%, titanium dioxide - 28.95%, macrogol 400 - 6.25%, iron oxide red - 1.00%; iron (II, III) oxide / iron oxide black - 0.75%; iron oxide yellow - 0.55%).

    Description:Round, biconvex tablets, covered with a film coat of gray-gray color. At the break, the core is white or almost white.
    Pharmacotherapeutic group:Antitumor agent protein tyrosine kinase inhibitor
    ATX: & nbsp

    L.01.X.E.02   Gefitinib

    Pharmacodynamics:

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

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

    There is evidence that gefitinib 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.

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

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

    When comparing gefitinib and a combination of carboplatin and paclitaxel in the first line of therapy for advanced non-small cell cancer(stage III B and IV) in Asian patients with a histological form of an adenocarcinoma tumor with a history of a smoker (who quit smoking ≥ 15 years ago and smoked ≤ 10 packs per year) gefitinib demonstrated statistically significant benefits in survival without signs of progression and an objective response compared to the combination of carboplatin and paclitaxel both in the entire 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.

    Confirmed sensitivity to gefitinib in the presence of frequent mutations of the epidermal growth factor receptor (deletion of 19 exon; L858R). 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

    Mutations were studied in samples of tumor tissue 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). Sensitivity (the proportion of patients with a mutation in tumor tissue that showed a mutation in circulating DNA) was 65.7% (confidence interval (CI): 55.8-74.7%), specificity (the proportion of patients with no mutation in the tumor tissue , in which there is no 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 using a test system EGFR Mutation Test Kit (sensitivity was 43.1%, specificity was 100%).

    The frequency of objective response to gefitinib therapy in patients of the Caucasoid race 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.

    Pharmacokinetics:

    Suction

    After ingestion, absorption is relatively slow. The maximum concentration of the drug in the blood plasma (CmOh) is reached within 3-7 hours (Topach) - Stationary concentration in the blood plasma (Css) is achieved on the 7 - 10 day of admission and exceeds the concentration after a single dose of 2 - 8 times. 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%.

    Distribution

    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%.

    Metabolism

    Gefitinib is exposed to oxidative metabolism by isoenzyme CYP3A4 systems of cytochrome P450.

    Metabolism gefitinib occurs in three ways:

    - metabolism N-propylmorpholine group;

    - demethylation of the methoxyl group to the quinazoline moiety;

    - oxidative dephosphorylation of a halogenated phenyl group.

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

    Excretion

    The total plasma clearance of gefitinib is approximately 500 mL / min. The average half-life (T1 / 2) is 41 hours.The drug is excreted mainly with feces. The kidneys produce less than 4% of the administered dose.

    Pharmacokinetics the separate patient groups

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

    Against the background of a daily dose of 250 mg of gefitinib, 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 liver failure. Data on patients with hepatic insufficiency of severe degree due to liver metastases suggest that the equilibrium concentration in these patients is similar to that in patients with normal liver function.

    The features of the action of gefitinib in patients with impaired hepatic function due to cirrhosis or hepatitis have not been studied.

    Indications:

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

    - Locally distributed 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 the period of breastfeeding.

    - 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 (there was an increased mortality from these diseases during treatment with gefitinib); with a weak or moderate increase in the activity of "liver" transaminases and bilirubin concentration; with lactase deficiency, lactose intolerance, glucose-galactose malabsorption (since lactose is contained in the drug form).

    Pregnancy and lactation:

    A drug Gefitinib-native contraindicated for use in pregnancy and in the period of breastfeeding.

    Dosing and Administration:

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

    In the event that the patient misses the next dose, the missed dose should be taken if the remaining dose remains at least 12 hours before the next dose.

    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 preparation Gefitinib-native can also be administered via a nasogastric tube.

    No dose adjustment is required Gefitinib-native depending on the age of patients, body weight, ethnicity and gender, as well as with moderate and severe hepatic insufficiency due to metastatic liver damage.

    Correction of the dose. In patients with poorly controlled diarrhea on the background of treatment or undesirable reactions from the skin, a short-term interruption in treatment (up to 14 days) is possible with the subsequent resumption of treatment with the drug Gefitinib-native in a dose of 250 mg per day.

    Side effects:

    The most common adverse reactions observed in more than 20% of cases with gefitinib are diarrhea, skin and acne, itching, dry skin.

    Usually, unwanted reactions appear during the first month of gefitinib and are usually reversible. Approximately 10% of patients have serious adverse reactions (3-4 degree of severity according to general toxicity criteria).

    The undesirable reactions presented below are listed in accordance with the damage to organs and organ systems and frequency of occurrence. The incidence of adverse reactions is estimated as follows: the occurrence of "very often" -> 10%; "often" -> 1% and <10%, "infrequently" -> 0.1% and <1%, "rarely" -> 0.01 % and <0.1%, "very rarely" - <0.01%, including individual messages, "frequency unknown."

    Disorders from the blood and lymphatic system: often - hematuria, nasal bleeding; infrequently - hypocoagulation and / or an increase in the frequency of bleeding when taking warfarin.

    Immune system disorders: infrequently - angioedema, hives.

    Disorders from the side of the organ of vision: often - conjunctivitis, blepharitis, xerophthalmia (mostly of a low degree of severity), reversible erosion of the cornea; infrequently - violation of the growth of eyelashes.

    Disturbances from the respiratory, thoracic and mediastinal systems: often - interstitial pneumonia (3-4 levels of toxicity, up to a lethal outcome).

    Disorders from the gastrointestinal tract: very often - diarrhea (in some cases, severe), nausea (mostly mild), vomiting (mostly mild to moderate), stomatitis (mostly mild), anorexia (mild to moderate), increased ALT (mostly of mild or moderate severity); often - dehydration (due to diarrhea, nausea, vomiting and anorexia), dry mouth (mostly mild), increased activity ACT (mainly weak or moderate stages of severity), an increase in the concentration of bilirubin (mostly of mild or moderate severity); infrequently - pancreatitis, perforation of the gastrointestinal tract, hepatitis.

    Disturbances from the skin and subcutaneous tissues: very often - 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, multiforme exudative erythema, cutaneous vasculitis.

    Disorders from the kidneys and urinary tract: often - an asymptomatic increase in the concentration of creatinine in the blood, proteinuria, cystitis; rarely - hemorrhagic cystitis.

    General disorders and disorders at the injection site: 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 unwanted reactions, mainly diarrhea and skin rash. Treatment is symptomatic. The antidote is not known.

    Interaction:

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

    Simultaneous administration of gefitinib and itraconazole (inhibitor of isoenzyme CYP3A4) leads to an increase of 80% AUC gefitinib, which can be clinically significant, since adverse events depend on dose and concentration.

    The simultaneous administration of gefitinib and preparations that promote a significant (≥ 5) and prolonged increase in the pH of gastric contents, resulted in a decrease AUC for gefitinib at 47 %.

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

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

    Special instructions:

    When deciding whether to prescribe the drug Gefitinib-native in the first line of therapy for locally advanced or metastatic non-small cell lung cancer, a mutation of the epidermal growth factor receptor in tumor tissue in all patients is recommended. If the tumor tissue sample is not available for investigation, circulating tumor DNA obtained from blood samples (plasma).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, the drug Gefitinib-native It can not be used in lieu of chemotherapy in patients with no mutation EGFR .

    Sometimes in patients taking gefitinib, there is 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, taking the drug Gefitinib-native terminate and the patient is given appropriate treatment. The most common development of interstitial lung lesions was observed in Japan (approximately 2% of cases in 27,000 patients taking gefitinib) compared with other countries (0.3% of cases among 39000 patients).

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

    Against the background of reception of gefitinib, an asymptomatic increase in the activity of "hepatic" transaminases and bilirubin concentration is observed, infrequently hepatitis develops. Individual cases of hepatic insufficiency, in some cases fatal, have been reported. In this connection, it is recommended to periodically evaluate the hepatic function. With a marked increase in the activity of transaminases and bilirubin concentration, the drug intake Gefitinib-native must be terminated.

    There are data on the incidence of cardiovascular complications in the use of gefitinib. The connection with gefitinib 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 and 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. With the confirmation of ulcerative keratitis, drug therapy Gefitinib-native should be paused. If the symptoms do not disappear or re-develop when the drug is resumed Gefitinib-native, should consider the possibility of a complete withdrawal of this therapy.

    When gefitinib was used in combination with radiotherapy as a first-line therapy in children with brainstem glioma or non-radically removed glioma of supratentorial localization, 4 cases (1 death) of cerebral hemorrhages were observed. Another case of cerebral hemorrhage was noted in a child with ependymoma with monotherapy with gefitinib. In adult patients with NSCLC in the treatment of gefitinib similar side effects are not documented in any case.

    There have been reports of cases of development of perforation of the digestive tract in patients on the background of receiving gefitinib. In most cases it was associated with other known risk factors, such as simultaneous reception of glucocorticosteroids, NSAIDs, a history of peptic ulcer disease, old age, smoking, and the presence of metastases to the large intestine at the site of perforation.

    Men and women with preserved reproductive potential during drug treatment Gefitinib-native and, at least, within 3 months after treatment should use reliable methods of contraception.

    Patients with rare hereditary diseases, such as lactose intolerance, lactase deficiency or malabsorption syndrome, should be prescribed a drug Gefitinib-native with caution, since the drug form contains lactose.

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

    Since when taking the drug Gefitinib-native such unwanted reactions as asthenia, nausea and vomiting can develop, caution should be exercised when driving vehicles and working with mechanisms, as well as when engaging in other potentially dangerous activities requiring increased concentration of attention and speed of psychomotor reactions.

    When these undesirable phenomena appear, one should refrain from performing these activities.

    Form release / dosage:

    Film-coated tablets, 250 mg.

    Packaging:

    For 30 tablets in bottles of polyethylene terephthalate, sealed with high density polyethylene caps.

    10 tablets per contour cell packaging made of polyvinyl chloride film and foil of aluminum laminated printed or polyvinyl chloride / polyvinylidene chloride film and aluminum foil laminated printed.

    For 1 bottle or 3 contour packs with the instructions for use are put in a cardboard box.

    Storage conditions:

    In the dark place at a temperature of no higher than 25 ° C.

    Keep out of the reach of children.

    Shelf life:

    2 years.

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

    Terms of leave from pharmacies:On prescription
    Registration number:LP-004258
    Date of registration:25.04.2017
    Expiration Date:25.04.2022
    The owner of the registration certificate:NATIVA, LLC NATIVA, LLC Russia
    Manufacturer: & nbsp
    Information update date: & nbsp01.06.2017
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