Gefitinib (Gefitinib)

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

    1 tablet, film-coated, contains:

    active substance: gefitinib 250.0 mg.

    auxiliary substances (core): lactose monohydrate 245.0 mg, microcrystalline cellulose 67.0 mg, povidone K-30 5.0 mg, croscarmellose sodium 20.0 mg, sodium lauryl sulfate 6.0 mg, magnesium stearate 7.0 mg;

    auxiliary substances (shell): film coating IC-S-2269 20.0 mg;

    film coating composition IC-S-2269: 60%, polyethylene glycol 12.00%, talc 4.908%, titanium dioxide (E 171) 23.0%, iron oxide yellow (E 172) 0.09%, iron oxide red (E 172) 0,002%.

    Description:

    Round, biconvex tablets, covered with a film membrane from pink to pink with a brownish color.

    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, radiotherapy and hormone therapy.

    Clinical evidence suggests that gefitinib has antitumor activity, statistically significantly increases the time to disease progression in patients with locally advanced or metastatic non-small cell carcinoma lung.

    Phase III study INTEREST showed that gefitinib, in comparison with docetaxel, provides a similar overall survival, more favorable tolerability profile and a better quality of life in previously treated patients with advanced non-small cell lung cancer.

    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. FROMmOh drug in the blood plasma is achieved within 3-7 hours. The average absolute bioavailability in patients - 59%. Eating does not affect the bioavailability of the drug.When the pH of gastric juice is 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. Binding to plasma proteins (with serum albumin and alpha 1-glycoprotein) is approximately 90%.

    Gefitinib is exposed to oxidative metabolism with the participation of isoenzyme CYP3A4 systems of cytochrome P450.

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

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

    The main metabolite, determined in the blood plasma is O-desmethylgefitinib, which has 14 times less pharmacological activity than gefitinib in terms of cell growth stimulated by epidermal growth factor,which makes unlikely its significant effect on the clinical activity of gefitinib. The total plasma clearance of gefitinib is approximately 500 mL / min. Average T1/2 - 41 h. The drug is excreted mainly by the intestine, less than 4% of the administered dose - by the kidneys. 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.

    On the background of a daily dose of gefitinib 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 hepatic insufficiency secondary degree. 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.

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

    Indications:

    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, the period of breastfeeding, children under 18 years.

    Carefully:

    - ANDdiopathic pulmonary fibrosis;

    - interstitial pneumonia;

    - pneumoconiosis;

    - post-radiation pneumonia;

    - drug pneumonia (there was an increased mortality rate from these diseases when treated with gefitinib);

    - increased activity of "liver" transaminases and bilirubin concentration;

    - lactose intolerance, lactase deficiency, glucose-galactose insufficiency.
    Pregnancy and lactation:

    Application during pregnancy and during breastfeeding is contraindicated.

    Dosing and Administration:

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

    If 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.

    No dosage adjustment is required depending on the patient's age, body weight, ethnicity, gender, kidney function, and moderate to severe hepatic insufficiency due to metastatic liver damage.

    Side effects:

    The most frequent undesirable phenomena observed more than 20% of cases, were diarrhea, skin (including acne) rash, itching, dryness skin. Usually adverse reactions appear during the first month of application and are usually reversible.

    In 8% of patients, there were serious adverse reactions (3-4 degrees of severity according to the general criteria of toxicity). However, only 1% of patients had therapy discontinued due to adverse reactions.

    The incidence of adverse events is determined according to the WHO classification: very often (≥ 10%); often (≥ 1 - <10%); infrequently (≥ 0.1 - <1%); rarely (≥ 0.01% - <0.1%); very rarely (<0.03%). The observed undesirable reactions are presented below.

    On the part of the organs of hematopoiesis: often - haematuria and epistaxis; infrequently - hypocoagulation and / or increased bleeding frequency when taking warfarin.

    From the side of the digestive system: very often - diarrhea (in some cases, pronounced), nausea; often - vomiting, anorexia, stomatitis, dehydration, an asymptomatic increase in the activity of "liver" transaminases, an increase in the concentration of bilirubin; rarely - pancreatitis, perforation of the gastrointestinal tract, hepatitis; very rarely - liver failure, including fatal.

    From the side of the organs of sight: often - conjunctivitis, blepharitis, xerophthalmus; infrequently - reversible erosion of the cornea, dysplasia of the eyelash; infrequently keratitis.

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

    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 Stephen-Johnson syndrome, cutaneous vasculitis; very rarely - toxic epidermal necrolysis and multiforme exudative erythema.

    From the side of the kidneys and urinary tract: often - increased creatinine in the blood, proteinuria, cystitis; rarely - hemorrhagic cystitis.

    Allergic reactions: very rarely - angioedema, hives.

    Other: very often - asthenia; infrequently, pyrexia.

    Overdose:

    Symptoms (possible): increased frequency and severity of some adverse reactions, mainly diarrhea and skin rash.

    Treatment: symptomatic therapy. The antidote is unknown.

    Interaction:

    Joint use of gefitinib and rifampicin (powerful isoenzyme inducer CYP3A4) leads to a decrease in the mean values AUFROM (area under the curve of drug concentration in the blood as a function of time) for gefitinib by 83%.

    The simultaneous use of gefitinib with potent inhibitors of isoenzyme CYP3A4 (ketoconazole, voriconazole, posaconazole, clarithromycin, telithromycin) increases the concentration of gefitinib in blood plasma. Thus, simultaneous use of gefitinib and itraconazole (inhibitor of isoenzyme CYP3A4) leads to an increase of 80% AUC gefitinib, which can be clinically significant, because The undesirable effects depend on the dose and concentration.

    The simultaneous use of gefitinib and drugs that significantly and continuously increased the pH of gastric contents led to to diminishing AUC for gefitinib by 47%.

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

    Drugs (drugs) that induce isoenzyme activity CYP3A4, can increase metabolism and reduce the concentration of gefitinib in the blood plasma. Thus, the simultaneous use of gefitinib with isozyme inducer preparations CYP3A4, such as phenytoin, carbamazepine, barbiturates, preparations of St. John's wort, perforated, may reduce the effectiveness of gefitinib.

    Research in vitro showed that gefitinib has some ability to inhibit isoenzyme activity CYP2D6. In the clinical trial, gefitinib was co-administered with metoprolol (substrate isoenzyme CYP2D6). This led to an increase in the impact of metoprolol by 35%.

    In patients taking concomitantly with gefitinib warfarin, it is necessary to monitor prothrombin time.

    Special instructions:

    Against the backdrop of treatment with gefitinib, there were cases of interstitial lung injury (including 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 injury, the medication is discontinued and appropriate treatment is prescribed.

    The most common development of interstitial lung lesions was observed in Japan (approximately 2% of cases in 27,000 patients taking the drug) compared with other countries (in 0.3% of cases among 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 treatment with gefitinib, there was an asymptomatic increase in the activity of "liver" transaminases, in connection with which it is necessary to periodically monitor liver function. With a marked increase in the activity of "liver" transaminases, the drug should be stopped.

    At the host gefitinib patients perforation of the gastrointestinal tract (GIT) are possible. In most cases, this is associated with other risk factors, including the use of steroid drugs, non-steroidal anti-inflammatory drugs, elderly age, smoking or intestinal metastases at perforation sites. If the patient confirms the presence of perforation of the gastrointestinal tract, the drug is stopped and appropriate treatment is prescribed.

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

    If any symptoms appear on the part of the eyes or when severe or prolonged diarrhea, nausea, vomiting, or anorexia develops, the patient should immediately consult a doctor.

    In patients with hard-to-resolve diarrhea, a short-term interruption in treatment (up to 14 days) is possible, with the subsequent resumption of treatment with the drug at a dose of 250 mg / day, against the background of treatment or adverse reactions from the skin.

    When used in combination with radiotherapy as 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 gefitinib. In adult patients with non-small cell lung cancer, no adverse events were reported with the drug.

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

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

    Patients should be warned about the possibility of emergence during treatment dizziness, fainting or vision disorders. If these symptoms occur, patients are advised to refrain from driving and practicing other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

    Form release / dosage:

    Tablets, film-coated, 250 mg.

    Packaging:

    For 10 and 30 tablets in a bottle of high-density polyethylene; 10 tablets per blister of aluminum foil.

    For 1 bottle or 1 blister, along with instructions for use in a cardboard box.

    Storage conditions:

    At a temperature of no higher than 25 ° C.

    Keep out of the reach of children.

    Shelf life:

    2 years.

    Do not use after expiry date.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-003076
    Date of registration:06.07.2015
    Expiration Date:06.07.2020
    Date of cancellation:2020-07-06
    The owner of the registration certificate:JODAS EKSPOIM, LLC JODAS EKSPOIM, LLC Russia
    Manufacturer: & nbsp
    Representation: & nbspJodas Expoim, Open CompanyJodas Expoim, Open Company
    Information update date: & nbsp03.04.2017
    Illustrated instructions
      Instructions
      Up