Iressa, 250 mg 30 pcs.

Pharmacodynamics

Antitumor drug. Being a selective inhibitor of epidermal growth factor receptor tyrosine kinase, which is expressed in many solid tumors, inhibits tumor growth, metastasis and angiogenesis as well as accelerates apoptosis of tumor cells.

Inhibits the growth of various human tumor cell lines and increases the antitumor activity of chemotherapeutic drugs, radiation and hormone therapy.

The clinical data suggest that Iressa® has an objective antitumor effect and statistically significantly increases time to disease progression in patients with locally advanced or metastatic non-small cell lung cancer.

Iressa®, compared with docetaxel, has been shown to provide 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, have an adenocarcinoma tumor morphologic variant, are female, or are of Asian race are more likely to benefit from Iressa® therapy. These clinical characteristics are also associated with a high frequency of epidermal tumor growth factor receptor mutations.

. When comparing Iressa® and carboplatin + paclitaxel combination in first-line therapy of advanced non-small cell lung cancer (stage IIIB and IV) in Asian patients with adenocarcinoma tumor histology with a history of heavy smoking (who had quit smoking ≥15 years ago and smoked ≤10 packs per year), Iressa® demonstrated statistically significant benefits in progression-free survival and objective response compared to the carboplatin + paclitaxel combination, both in the entire group and in the group of patients in whom epidermal growth factor receptor mutations were identified.

Pharmacokinetics

Intake

After oral administration, absorption is relatively slow. Cmax in blood plasma is reached within 3-7 hours. Absolute bioavailability is on average 59%. Food intake does not affect the bioavailability of the drug. When gastric pH index is higher than 5, the bioavailability of gefitinib decreased by 47%.

Distribution

The regular use of the drug 1 time/day leads to an increase in the concentration by 2-8 times compared to a single dose. Css is reached after 7-10 doses.

The Vd of gefitinib when Css is reached is 1400 L, indicating extensive distribution of the drug in the tissues.

The binding to plasma proteins (serum albumin and α1-glycoprotein) is approximately 90%.

Metabolism

Gefitinib undergoes oxidative metabolism via CYP3A4 isoenzyme.

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

The main metabolite detected in human plasma is O-desmethylhefitinib. The metabolite has 14 times less activity than gefitinib against epidermal growth factor-stimulated cell growth, which makes it unlikely to have a significant effect on the clinical activity of gefitinib.

Elimination

The total plasma clearance of gefitinib is approximately 500 mL/min. T1/2 is on average 41 h. The drug is excreted mainly in the feces. Less than 4% of the administered dose is excreted in the urine.

Pharmacokinetics in special clinical cases

There is no association between the lower Css level of the drug and age, body weight, sex, ethnicity or creatinine clearance.

On daily administration of Iressa at a dose of 250 mg Css, time to reach and total plasma clearance were similar for the groups of patients with normal liver function and with moderate hepatic impairment. Data from 4 patients with severe hepatic failure due to liver metastases suggest that Css in these patients is similar to that in patients with normal liver function.

The specific pharmacokinetics of gefitinib in patients with impaired liver function due to cirrhosis or hepatitis have not been studied.

Indications

• Local 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 first-line therapy;
• Local or metastatic non-small cell lung cancer refractory to chemotherapy regimens containing platinum derivatives.

Active ingredient

Gefitinib

Composition

Active ingredient:gefitinib 250 mg.

Associated substances:

Lactose monohydrate – 163.5 mg,

Microcrystalline cellulose – 50 mg,

croscarmellose sodium – 20 mg,

povidone (K29-32) – 10 mg,

/p>

sodium lauryl sulfate – 1.5 mg,

magnesium stearate – 5 mg.

Composition of the film coating:

Hypromellose – 7.65 mg, macrogol 300 – 1.5 mg, iron oxide red (E172) – 0.9 mg, iron oxide yellow (E172) – 0.9 mg, titanium dioxide (E171) – 0.5 mg.

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How to take, the dosage

The drug is administered orally at 250 mg 1 time per day, regardless of meals.

If a patient misses another dose of the drug, the missed dose should be taken if at least 12 hours remain until the next dose. Do not take a double dose of the drug to make up for a missed dose.

The tablet may be dissolved in 100 ml of drinking (non-carbonated) water before taking. Other liquids should not be used. For proper dissolution you need to put the tablet in water, without crushing it, stir until the complete dissolution (about 15 minutes) and immediately drink the resulting suspension. Pour another half a glass of water, rinse the walls and drink the resulting suspension. Iressa® suspension may also be administered through a nasogastric tube.

Iressa® dose adjustment is not required depending on the patient’s age, body weight, ethnicity, sex, renal function and in moderate to severe hepatic impairment due to metastatic liver injury.

In patients with poorly controlled diarrhea during treatment or with adverse skin reactions a short-term treatment interruption is possible (up to 14 days) followed by restart of Iressa® at a dose of 250 mg/day.

Interaction

Co-administration of gefitinib and rifampicin (potent inducer of CYP3A4 isoenzyme) leads to a decrease in the average AUC for gefitinib by 83%.

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

The concomitant administration of gefitinib and drugs that contribute to a significant (≥5) and prolonged increase in gastric pH resulted in a 47% decrease in AUC for gefitinib.

In co-administration of gefitinib and vinorelbine, the neutropenic effect of vinorelbine may be enhanced.

Drugs that induce CYP3A4 isoenzyme activity may increase metabolism and decrease plasma concentration of gefitinib. Thus, concomitant administration of gefitinib with drugs inducers of CYP3A4 isoenzyme, such as phenytoin, carbamazepine, barbiturates, tincture of Hypericum may decrease the effectiveness of gefitinib.

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Special Instructions

The determination of EGFR (epidermal growth factor receptor) mutations in tumor tissue in all patients is recommended when deciding whether to prescribe Iressa® as first-line therapy for locally advanced or metastatic non-small cell lung cancer. For mutation detection, it is important that a validated and reliable methodology is chosen to minimize possible both false negatives and false positives. In first-line therapy, Iressa® cannot be used instead of chemotherapy in patients with no EGFR mutation .

In some cases, interstitial lung damage, in some cases fatal, has been reported in patients taking Iressa®. If symptoms such as dyspnea, cough, fever increase, the drug should be discontinued and an examination should be performed immediately. If the patient is confirmed with interstitial lung disease, the drug Iressa® should be discontinued and an appropriate treatment should be prescribed.

The highest incidence of interstitial lung disease has been seen in Japan (approximately 2% of 27,000 Iressa® patients) compared to other countries (0.3% of 39,000 patients).

Factors increasing the risk of interstitial lung damage included: Smoking, severe general condition (PS > 2), normal lung tissue according to CT scan < 50%, duration of disease (non-small cell lung cancer) < 6 months, history of interstitial pneumonia, advanced age ( > 55 years), comorbid cardiovascular disease.

An asymptomatic increase in liver transaminase activity and bilirubin level has been noted while taking Iressa® , infrequently hepatitis developed. Single cases of liver failure have been reported, in some cases with lethal outcome. In this regard, it is recommended to periodically assess hepatic function. In marked increase of transaminase activity and bilirubin level the drug should be discontinued.

In clinical trials of Iressa® there have been reports of cardiovascular complications. The association with taking Iressa® has not been established.

In patients taking warfarin prothrombin time should be monitored regularly.

Patients should see a physician immediately if any visual symptoms occur or if severe or prolonged diarrhea, nausea, vomiting, or anorexia develop.

In the use of Iressa® in combination with radiotherapy as first-line therapy in children with brainstem glioma or nonradically removed supratentorial glioma, 4 cases (one fatal) of cerebral hemorrhage have been reported. Another case of cerebral hemorrhage was reported in a child with an ependymoma during monotherapy with Iressa®. In adult patients with non-small cell lung cancer no such adverse events have been reported with Iressa® treatment.

In single cases of gastrointestinal perforation have been reported in patients with such risk factors as concomitant use of steroids, NSAIDs, a history of peptic ulcer disease, advanced age, smoking, and the presence of metastases to the colon at the site of perforation. However, no causal relation between the listed phenomena and administration of Iressa® was established.

In patients with rare hereditary diseases, such as lactose intolerance, lactase deficiency or malabsorption syndrome, Iressa® should be used with caution because of the lactose content.

Ireessa® influences on the ability to drive vehicles and other mechanisms requiring high concentration

We should be careful when driving and engaging in other potentially dangerous activities requiring high concentration and quick psychomotor reactions while using Iressa® because adverse reactions such as asthenia, nausea and vomiting may develop during the therapy.

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Contraindications

• Pregnancy
• lactation period
• child and adolescent age (safety and effectiveness in this group of patients has not been evaluated);
• high sensitivity to gefitinib or other drug components.

With caution: The drug should be used in idiopathic pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, postradiation pneumonia, drug-induced pneumonia (increased mortality rate from these diseases during treatment with Iressa® has been noted); with mild to moderate increase of liver transaminase activity and bilirubin level.

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Side effects

The most common adverse effects, observed in more than 20% of cases, were diarrhea, skin and acne rashes, itching, and dry skin.

In general, adverse reactions occur within the first month of using the drug and are usually reversible. Approximately 10% of patients had serious adverse reactions (grade 3-4 severity according to the general criteria for toxicity).

However, only 3% of patients had therapy discontinued due to adverse reactions.

The observed adverse reactions are presented below.

Determine the frequency of adverse reactions:

• very common (≥10%);
• frequent (≥1% to < 10%);
• infrequently (≥0.1% – < 1%);
• infrequently (≥0.01% – < 0.1%).

With the clotting system: often – hematuria and nasal bleeding; infrequent – hypocoagulation and/or increased frequency of bleeding during administration of warfarin.

Digestive system disorders: very common – diarrhea (pronounced in some cases), nausea (mostly mild to moderate), vomiting (mostly mild to moderate), stomatitis (mostly mild), anorexia (mild to moderate), increased ALT activity (mostly mild to moderate); common – dehydration (due to diarrhea, nausea, vomiting, and anorexia), dry mouth (mostly mild), elevated ACT activity (mostly mild or moderate), elevated bilirubin levels (mostly mild or moderate); infrequent – pancreatitis, hepatitis (single cases of liver failure, in some cases with lethal outcome have been reported).

In the organs of vision: frequently – conjunctivitis, blepharitis, xerophthalmia (mostly of mild degree of intensity); infrequent – reversible corneal erosion, disorder of eyelash growth.

Respiratory system: often – interstitial pneumonia (degree 3-4 of toxicity, up to fatal).

Urinary system disorders: often – asymptomatic elevation of creatinine in the blood, proteinuria.

Dermatological reactions: very common – rash (pustular), itching, dry skin, including formation of cracks with erythema; common – changes in the nails, alopecia; rarely – bullous skin changes, including toxic epidermal necrolysis, Stevens-Johnson syndrome and erythema multiforme exudative, cutaneous vasculitis.

Allergic reactions: infrequent – angioedema, urticaria.

Others: very common – asthenia (mostly mild), often – increase in body temperature.

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Overdose

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

Treatment: symptomatic therapy is carried out. An antidote is not known.

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Pregnancy use

The use of Iressa® is contraindicated in pregnancy and during lactation.

Men and women of childbearing age should use reliable methods of contraception while taking Iressa and for at least 3 months after treatment.

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