Gefiba^® Onco (Tablets) Instructions for Use

Marketing Authorization Holder

Hetero Labs, Limited (India)

Manufactured By

Hetero Labs, Limited (India)

Labeled By

HETERO LABS, Limited (India)

Or

MAKIZ-PHARMA, LLC (Russia)

ATC Code

L01EB01 (Gefitinib)

Active Substance

Gefitinib (Rec.INN registered by WHO)

Dosage Form

Gefiba® Onco

Film-coated tablets, 250 mg: 30 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets brown in color, round, biconvex, with an engraving “H” on one side and “12” on the other side.

Excipients: mannitol – 97 mg, microcrystalline cellulose (PH-101) – 23 mg, sodium carboxymethyl starch – 12 mg, povidone K30 – 10 mg, colloidal silicon dioxide – 2 mg, calcium stearate – 6 mg.

Film coating composition Opadry II brown 85F86748 (partially hydrolyzed polyvinyl alcohol (E1203) – 40%, macrogol (E1521) – 20.2%, titanium dioxide (E171) – 15.91%, talc (E553b) – 14.8%, iron oxide red dye (E172) – 8.5%, iron oxide yellow dye (E172) – 0.56%, iron oxide black dye (E172) – 0.03%) – 8 mg.

10 pcs. – blisters (3) – cardboard packs.
30 pcs. – bottles (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, which are expressed 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 hormonal 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 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 through three pathways: 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

Take orally at a dose of 250 mg once daily.

Administer regardless of meals.

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

If you miss a dose, take it as soon as you remember unless it is less than 12 hours until the next scheduled dose; in that case, skip the missed dose and continue with the regular schedule. Do not take a double dose to make up for a missed one.

For poorly controlled diarrhea or severe skin adverse reactions, a temporary treatment interruption of up to 14 days is permitted.

Following symptom improvement, resume treatment at the same dose of 250 mg once daily.

In patients with moderate to severe hepatic impairment, administer with caution and monitor liver function regularly.

No dosage adjustment is required for patients with renal impairment or in the geriatric population.

Avoid concomitant use of potent CYP3A4 inducers (e.g., rifampicin, phenytoin) due to risk of reduced efficacy; if co-administration is unavoidable, consider a dose increase under close monitoring.

Exercise caution with drugs that significantly elevate gastric pH (e.g., proton pump inhibitors) as they may reduce gefitinib bioavailability.

Adverse Reactions

From the blood coagulation system often – hematuria and nosebleeds; 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 and including fatal outcome).

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

Allergic reactions very rarely – angioedema, urticaria.

Other often – asthenia, increased body temperature.

Contraindications

Pregnancy, lactation (breastfeeding), childhood and adolescence, increased sensitivity 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, post-radiation pneumonia, 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, or fever worsen, the use of the drug should be discontinued and the patient should be examined immediately. If interstitial lung disease is confirmed, Gefitinib should be discontinued and appropriate treatment prescribed.

Factors that increase the risk of developing interstitial lung disease have been 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 gastric pH, 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 plasma concentration of gefitinib. 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.