Langerra (Tablets) Instructions for Use

Marketing Authorization Holder

Pharma-Sintez, JSC (Russia)

Manufactured By

Pharma-Sintez, LLC (Russia)

Or

Nanopharma Development, LLC (Russia)

Packaging and Quality Control Release

Pharma-Sintez, LLC (Russia)

ATC Code

L01EB01 (Gefitinib)

Active Substance

Gefitinib (Rec.INN WHO registered)

Dosage Form

Langerra

Film-coated tablets, 250 mg: 30 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white, round, biconvex; the core on the cross-section is white to almost white.

Excipients: lactose monohydrate – 163.5 mg, microcrystalline cellulose type 101 – 50 mg, croscarmellose sodium – 20 mg, povidone K30 – 10 mg, sodium lauryl sulfate – 1.5 mg, magnesium stearate – 5 mg.

Film coating composition Opadry AMB II 88A180021 white (polyvinyl alcohol – 39.5%, talc – 38%, titanium dioxide – 15%, glycerol monocaprylocaprate type 1/glycerol fatty acid esters – 4.5%, sodium lauryl sulfate – 3%) – 15 mg.

10 pcs. – blister packs (3) – cardboard packs.
30 pcs. – polymer jars (1) – cardboard packs.

Clinical-Pharmacological Group

Antitumor drug. Protein kinase inhibitor

Pharmacotherapeutic Group

Antineoplastic agents; protein kinase inhibitors; epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors

Pharmacological Action

Antitumor agent. Being a selective inhibitor of tyrosine kinase of epidermal growth factor receptors, the expression of which is observed in many solid tumors, it inhibits tumor growth, metastasis and angiogenesis, and also accelerates apoptosis of tumor cells.

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

Clinical data indicate that Gefitinib statistically significantly increases the time to disease progression in patients with locally advanced or metastatic non-small cell lung cancer.

Pharmacokinetics

After oral administration, absorption is relatively slow. C_max in blood plasma is reached within 3-7 hours. The absolute bioavailability averages 59%. Food intake does not affect bioavailability. When the gastric pH is above 5, the bioavailability of gefitinib decreased by 47%.

Regular use of the drug once/day leads to an increase in concentration by 2-8 times compared to a single dose. C_ss is achieved after taking 7-10 doses. The V_d of gefitinib at C_ss is 1400 L, which indicates extensive distribution of the drug in tissues. Binding to plasma proteins (with serum albumin and α₁-glycoprotein) is approximately 90%.

Gefitinib undergoes oxidative metabolism with the participation of the CYP3A4 isoenzyme. The metabolism of gefitinib occurs in three ways: metabolism of the N-propylmorpholine group, demethylation of the methoxy group on the quinazoline part, and oxidative defluorination of the halogenated phenyl group. The main metabolite determined in human plasma is O-desmethylgefitinib. The metabolite has 14 times less activity compared to gefitinib in relation to epidermal growth factor-stimulated cell growth, which makes its significant impact on the clinical activity of gefitinib unlikely.

The total plasma clearance of gefitinib is approximately 500 ml/min. T_1/2 averages 41 hours. It is excreted mainly in the feces; less than 4% of the administered dose is excreted in the urine.

Indications

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

ICD codes

Dosage Regimen

Administer orally at a dose of 250 mg once daily.

Take the tablet regardless of meals.

Swallow the tablet whole with a glass of water; do not crush or chew.

For poorly controlled diarrhea or severe skin adverse reactions, institute a treatment interruption for up to 14 days.

Following the interruption, resume therapy at the 250 mg once-daily dose.

In patients requiring medications that elevate gastric pH (e.g., proton pump inhibitors), be aware of a potential decrease in gefitinib bioavailability.

Avoid concomitant use with strong CYP3A4 inducers (e.g., rifampicin, phenytoin, St. John’s wort) due to the risk of reduced efficacy.

Exercise caution with strong CYP3A4 inhibitors (e.g., itraconazole) as they may increase gefitinib exposure and the risk of adverse effects.

Monitor prothrombin time regularly in patients concurrently taking warfarin.

Adverse Reactions

From the blood coagulation system often – hematuria and epistaxis; infrequently – hypocoagulation and/or increased frequency of bleeding while taking warfarin.

From the digestive system very often – diarrhea (in some cases – severe), nausea; often – vomiting, anorexia, stomatitis, dehydration, asymptomatic increase in liver transaminase activity; rarely – pancreatitis.

From the organ of vision often – conjunctivitis, blepharitis; infrequently – reversible corneal erosion, impaired eyelash growth.

From the respiratory system infrequently – interstitial pneumonia (grade 3-4 toxicity, up to death).

Dermatological reactions very often – rash (pustular), itching, dry skin against a background of erythema; often – nail changes, alopecia; very rarely – toxic epidermal necrolysis and erythema multiforme exudativum.

Allergic reactions very rarely – angioedema, urticaria.

Other often – asthenia, increased body temperature.

Contraindications

Pregnancy, lactation (breastfeeding), childhood and adolescence, hypersensitivity to gefitinib.

Use in Pregnancy and Lactation

Contraindicated during pregnancy and lactation. Men and women of childbearing potential should use reliable methods of contraception during the use of gefitinib and for at least 3 months after treatment.

Use in Hepatic Impairment

Liver function should be periodically evaluated during treatment. In case of a significant increase in transaminase activity, the use of gefitinib should be discontinued.

Pediatric Use

Contraindicated in childhood and adolescence.

Geriatric Use

Elderly age (over 55 years) is a factor that increases the risk of developing interstitial lung disease.

Special Precautions

Use with caution in idiopathic pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonitis, drug-induced pneumonia (increased mortality from these diseases has been noted during treatment with gefitinib); with increased activity of liver transaminases.

If symptoms such as shortness of breath, cough, fever increase, the use of the drug should be discontinued and the patient should be immediately examined. If interstitial lung disease is confirmed, Gefitinib should be discontinued and appropriate treatment prescribed.

Among the factors that increase the risk of developing interstitial lung disease were noted: smoking, severe general condition, normal lung tissue according to computed tomography < 50%, duration of disease < 6 months, history of interstitial pneumonia, elderly age (over 55 years), concomitant cardiovascular diseases.

Liver function should be periodically evaluated during treatment. In case of a significant increase in transaminase activity, the use of gefitinib should be discontinued.

In patients taking warfarin, regular monitoring of prothrombin time is necessary during treatment with gefitinib.

Drug Interactions

With simultaneous use of gefitinib and rifampicin (a potent inducer of the CYP3A4 isoenzyme), the mean AUC of gefitinib decreases by 83%.

Itraconazole (an inhibitor of the CYP3A4 isoenzyme) increases the AUC of gefitinib by 80%, which may be clinically significant, because side effects are dose- and concentration-dependent.

With simultaneous use with drugs that cause a significant and prolonged increase in the pH of gastric contents, a decrease in the AUC of gefitinib by 47% was observed.

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

Drugs that induce the activity of the CYP3A4 isoenzyme can enhance metabolism and reduce the concentration of gefitinib in blood plasma. Therefore, with simultaneous use of gefitinib with inducers of the CYP3A4 isoenzyme, such as phenytoin, carbamazepine, rifampicin, barbiturates, St. John’s wort tincture, a decrease in the effectiveness of gefitinib is possible.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.