Tolgecit (Lyophilisate) Instructions for Use

ATC Code

L01BC05 (Gemcitabine)

Active Substance

Gemcitabine (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antitumor drug. Antimetabolite

Pharmacotherapeutic Group

Antineoplastic agent, antimetabolite

Pharmacological Action

Antineoplastic agent. It has a cytostatic effect, which is associated with the inhibition of DNA synthesis. In the cell, it is metabolized to active diphosphate and triphosphate nucleosides.

Diphosphate nucleosides inhibit the action of ribonucleotide reductase, which is involved in the production of deoxynucleoside triphosphates necessary for DNA synthesis in the cell, leading to a decrease in their concentration in the cell.

Triphosphate nucleosides actively compete for incorporation into the DNA chain and can also be incorporated into RNA.

After the incorporation of intracellular gemcitabine metabolites into the DNA chain, one additional nucleotide is added to its growing strands, which leads to complete inhibition of further DNA synthesis and programmed cell death.

Pharmacokinetics

After IV infusion of gemcitabine at doses of 500-2592 mg/m² over 0.4-1.2 hours, the C_max in plasma was 3.2-45.5 µg/ml and was determined within 5 minutes after the end of the infusion.

The V_d in the central compartment is 12.4 L/m² in women and 17.5 L/m² in men (individual variation – 91.9%). The V_d in the peripheral compartment is 47.4 L/m² and does not depend on gender. Protein binding is practically absent.

Systemic clearance varies from 29.2 L/h/m² to 92.2 L/h/m². Clearance in women is approximately 25% lower than in men.

Less than 10% is excreted unchanged in the urine. Renal clearance is 2-7 L/h/m². T_1/2 depends on age and gender and is 42-94 minutes. When administered once a week, Gemcitabine does not accumulate.

Gemcitabine is rapidly metabolized by cytidine deaminase in the liver, kidneys, blood, and other tissues.

During the intracellular metabolism of the active substance, mono-, di-, and triphosphates of gemcitabine are formed, which have pharmacological activity. These metabolites are not detected in plasma or urine.

The main metabolite, 2-deoxy-2,2-difluorouridine, has no pharmacological activity and is detected in plasma and urine.

Indications

Non-small cell lung cancer (stages IIIa-IV); advanced carcinomas of the pancreas.

ICD codes

Dosage Regimen

Administer Tolgecit (gemcitabine) lyophilisate intravenously only after reconstitution and dilution.

Determine the dose individually based on body surface area, calculated using the patient’s actual height and weight.

For non-small cell lung cancer, the standard regimen is 1000 mg/m². Infuse intravenously over 30 minutes. Repeat this dose on days 1, 8, and 15 of each 28-day cycle, in combination with other chemotherapeutic agents.

For advanced pancreatic carcinoma, the standard regimen is 1000 mg/m². Infuse intravenously over 30 minutes. Administer once weekly for up to 7 weeks, followed by a one-week rest. Subsequent cycles consist of once-weekly injections for 3 consecutive weeks out of every 4.

Monitor complete blood count prior to each dose. Adjust or withhold therapy based on the degree of hematologic toxicity. For absolute granulocyte count below 1000 x 10⁶/L or platelet count below 100,000 x 10⁶/L, omit the dose.

Reduce the dose for patients experiencing severe non-hematologic toxicity, excluding nausea and vomiting.

Use with caution and consider dose adjustments in patients with impaired renal or hepatic function.

Reconstitute the lyophilisate with 0.9% Sodium Chloride Injection without preservatives. Further dilute the reconstituted solution with 0.9% Sodium Chloride Injection to a final concentration as low as 0.1 mg/mL. Administer the diluted solution within 24 hours of reconstitution when stored refrigerated. Do not refrigerate the final solution if it will be administered within 24 hours. Discard any unused portion.

Adverse Reactions

From the hematopoietic system leukopenia, thrombocytopenia, anemia.

From the digestive system nausea, vomiting, diarrhea; rarely – constipation.

From the urinary system proteinuria, hematuria; rarely – peripheral edema; in isolated cases – renal failure.

Dermatological reactions skin rash, itching, alopecia, stomatitis; rarely – desquamation, vesicular rash, eczema.

From laboratory parameters transient increase in the activity of hepatic transaminases, alkaline phosphatase, increase in plasma bilirubin concentration.

From the respiratory system rarely – bronchospasm, dyspnea.

From the CNS and peripheral nervous system rarely – drowsiness, weakness, paresthesia.

From the cardiovascular system rarely – arterial hypotension, pulmonary edema; in isolated cases – myocardial infarction, arrhythmias.

Other flu-like syndrome.

Contraindications

Hypersensitivity to gemcitabine.

Use in Pregnancy and Lactation

The safety of gemcitabine during human pregnancy has not been studied.

Experimental studies have shown that Gemcitabine has embryo- and fetotoxic effects, negatively affects the course of pregnancy and postnatal development.

The use of gemcitabine during pregnancy should be avoided. Women of childbearing potential should use reliable methods of contraception during treatment.

If it is necessary to use during lactation, the issue of discontinuing breastfeeding should be decided.

Use in Hepatic Impairment

Use with caution in case of impaired liver function, with periodic monitoring of its functional state.

Use in Renal Impairment

Use with caution in case of impaired renal function, with periodic monitoring of their functional state.

Pediatric Use

The safety and efficacy of gemcitabine in children have not been studied.

Special Precautions

It has some activity in advanced stages of breast cancer, ovarian cancer, kidney cancer, bladder cancer, and prostate cancer, as well as small cell lung cancer.

Use with caution in case of hematopoietic disorders; impaired liver and/or kidney function. During treatment, peripheral blood counts should be monitored regularly. If a toxic hematological effect develops, dose regimen adjustment is required depending on the degree of leukopenia and thrombocytopenia.

The safety and efficacy of gemcitabine in children have not been studied.

Effect on the ability to drive vehicles and operate machinery

During treatment, one should refrain from potentially hazardous activities that require increased attention and speed of psychomotor reactions.

Drug Interactions

The risk of development and severity of leukopenia and thrombocytopenia increases after prior therapy with cytostatics.

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.