Gemtaz (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Sun Pharmaceutical Industries, Ltd. (India)

ATC Code

L01BC05 (Gemcitabine)

Active Substance

Gemcitabine

Dosage Forms

	Gemtaz	Lyophilisate for preparation of solution for infusion 200 mg: vial 1 pc.
		Lyophilisate for preparation of solution for infusion 1000 mg: vial 1 pc.

Dosage Form, Packaging, and Composition

Lyophilisate for preparation of solution for infusion as a compact mass or powder of white or almost white color.

Excipients: mannitol – 200 mg, sodium acetate – 12.5 mg, hydrochloric acid – q.s. to pH 2.7-3.3 and sodium hydroxide – to pH 2.7-3.3.

Glass vials with a capacity of 10 ml (1) – cardboard packs.

Lyophilisate for preparation of solution for infusion as a compact mass or powder of white or almost white color.

Excipients: mannitol – 1000 mg, sodium acetate – 62.5 mg, hydrochloric acid – q.s. to pH 2.7-3.3 and sodium hydroxide – q.s. to pH 2.7-3.3.

Glass vials with a capacity of 50 ml (1) – cardboard packs.

Clinical-Pharmacological Group

Antitumor drug. Antimetabolite

Pharmacotherapeutic Group

Antineoplastic agent, antimetabolite

Pharmacological Action

Antitumor drug, an antimetabolite of the pyrimidine analog group, suppresses DNA synthesis. It exhibits cycle specificity, acting on cells in the S and G1/S phases. It is metabolized in the cell under the action of nucleoside kinases to active diphosphate and triphosphate nucleosides. Diphosphate nucleosides inhibit the action of ribonucleotide reductase (the only enzyme that catalyzes the formation of deoxynucleoside triphosphates necessary for DNA synthesis). Triphosphate nucleosides are capable of incorporating into the DNA chain (to a lesser extent RNA), which leads to the cessation of further DNA synthesis and programmed cell lysis (apoptosis).

In pancreatic cancer, it is considered a first-line drug: monotherapy causes clinical improvement in 25-40% of patients, and partial remission lasting 11-12 weeks in 10-15% of patients: 23% of patients live more than one year. When gemcitabine is combined with cisplatin, the treatment efficacy increases to 69%. Gemcitabine is also a strong radiosensitizing agent even at concentrations lower than cytotoxic ones.

Pharmacokinetics

Distribution

C_max of gemcitabine (from 3.2 µg/ml to 45.5 µg/ml) is reached 5 minutes after the end of the infusion. Pharmacokinetic analysis of single and multiple dose studies shows that V_d largely depends on gender. The binding of gemcitabine to plasma proteins is insignificant.

Metabolism

In the body, Gemcitabine is rapidly metabolized by cytidine deaminase in the liver, kidneys, blood, and other tissues, resulting in the formation of Gemcitabine mono-, di-, and triphosphates, of which Gemcitabine di- and triphosphates are considered active.

Excretion

Gemcitabine is rapidly excreted from the body by the kidneys mainly as the inactive metabolite 2′-deoxy-2′,2′-difluorouridine. Less than 10% of the intravenously administered dose is found in the urine as unchanged gemcitabine. Systemic clearance, which ranges from approximately 30 L/h/m² to 90 L/h/m², depends on age and gender. T_1/2 ranges from 42 minutes to 94 minutes. When the recommended dosing regimen is followed, complete elimination of gemcitabine occurs within 5-11 hours from the start of the infusion. When administered once a week, Gemcitabine does not accumulate in the body.

Pharmacokinetics in special clinical cases

When gemcitabine and paclitaxel are administered together, the pharmacokinetics of the drugs do not change.

When gemcitabine and carboplatin are administered together, the pharmacokinetics of gemcitabine do not change.

Mild and moderate renal impairment (CrCl 30-80 ml/min) does not significantly affect the pharmacokinetics of gemcitabine.

Indications

• Locally advanced or metastatic non-small cell lung cancer as first-line therapy in combination with cisplatin, as well as in monotherapy in elderly patients with a functional status of 2 (according to the ECOG-WHO scale);
• Inoperable, locally recurrent or metastatic breast cancer after neoadjuvant and/or adjuvant therapy including anthracyclines, in the absence of contraindications to their use, as part of combination therapy with paclitaxel;
• Locally advanced or metastatic urothelial cancer (cancer of the bladder, renal pelvis, ureters, urethra);
• Locally advanced or metastatic ovarian cancer as monotherapy or in combination with carboplatin in patients with disease progression after first-line platinum-based therapy;
• Locally advanced or metastatic pancreatic cancer;
• Locally advanced or metastatic cervical cancer.

ICD codes

Dosage Regimen

Gemtaz is administered intravenously by drip over 30 minutes.

Locally advanced or metastatic non-small cell lung cancer as first-line therapy in combination with cisplatin, as well as in monotherapy in elderly patients with a functional status of 2 (according to the ECOG-WHO scale)

For monotherapy, the recommended dose of the drug is 1000 mg/m² on days 1, 8, and 15 of each 28-day cycle.

For combination therapy with cisplatin, the recommended dose of the drug is 1250 mg/m² on days 1 and 8 of each 21-day cycle or 1000 mg/m² on days 1, 8, and 15 of each 28-day cycle. Cisplatin is administered at a dose of 70 mg/m² on day 1 of the cycle with hydration after gemcitabine infusion.

For combination therapy with carboplatin, the recommended dose of the drug is 1000 mg/m² or 1200 mg/m² on days 1 and 8 of each 21-day cycle. Carboplatin is administered at a dose of 5 mg/ml×min on day 1 of the cycle after gemcitabine infusion.

Inoperable, locally recurrent or metastatic breast cancer after neoadjuvant and/or adjuvant therapy including anthracyclines, in the absence of contraindications to their use, as part of combination therapy with paclitaxel

As first-line therapy for disease progression after neoadjuvant therapy including anthracyclines, the recommended dose of the drug is 1250 mg/m² on days 1 and 8 in combination with paclitaxel at a dose of 175 mg/m², which is administered after gemcitabine administration on day 1 of each 21-day cycle by intravenous drip over approximately 3 hours.

Locally advanced or metastatic urothelial cancer (cancer of the bladder, renal pelvis, ureters, urethra)

For monotherapy, the recommended dose of the drug is 1250 mg/m² on days 1, 8, and 15 of each 28-day cycle.

For combination therapy, the recommended dose of the drug is 1000 mg/m² on days 1, 8, and 15 in combination with cisplatin, which is administered at a dose of 70 mg/m² immediately after gemcitabine infusion on day 1 or day 2 of each 28-day cycle.

Locally advanced or metastatic ovarian cancer as monotherapy or in combination with carboplatin in patients with disease progression after first-line platinum-based therapy

For monotherapy, the recommended dose of the drug is 800-1250 mg/m² on days 1, 8, and 15 of each 28-day cycle.

For combination therapy, the recommended dose of the drug is 1000 mg/m² on days 1 and 8 in combination with carboplatin at a dose of 4 mg/ml×min, which is administered immediately after gemcitabine infusion on day 1 of each 21-day cycle.

Locally advanced or metastatic pancreatic cancer

For monotherapy, the recommended dose of the drug is 1000 mg/m² once a week for 7 weeks followed by a one-week break. Then the drug is administered on days 1, 8, and 15 of each 28-day cycle.

Locally advanced or metastatic cervical cancer

As part of combination therapy for locally advanced cancer (neoadjuvantly) and for metastatic cancer, Gemcitabine is administered at a dose of 1250 mg/m² on days 1 and 8 of each 21-day cycle. Cisplatin is administered at a dose of 70 mg/m² after gemcitabine administration on day 1 of the cycle with hyperhydration.

For locally advanced cancer with concurrent radiation therapy, Gemcitabine is administered once a week for 6 weeks at a dose of 125 mg/m² followed by (immediately after gemcitabine administration) administration of cisplatin at a dose of 40 mg/m² 1-2 hours before the start of radiation therapy. Radiation therapy is administered in 28 fractions, with a single focal dose of 1.8 Gy, 5 days a week to a total focal dose of 50.4 Gy.

Dosage adjustment of the drug due to hematological toxicity

Start of treatment cycle

Regardless of the indication, platelet and granulocyte counts must be assessed before each administration of the drug.

The condition for starting treatment is an absolute neutrophil count of at least 1500/µl and a platelet count of at least 100,000/µl.

In case of hematological toxicity during the therapy cycle, the dose of gemcitabine may be reduced or its administration delayed according to the following recommendations.

* When the neutrophil count increases to 500/µl and platelets to 50,000/µl, gemcitabine administration can be continued within the cycle.

* Treatment within the cycle is not resumed. The next administration of gemcitabine is carried out on day 1 of the next cycle when the neutrophil count recovers to at least 1500/µl and platelets to 100,000/µl.

* Treatment within the cycle is not resumed. The next administration of gemcitabine is carried out on day 1 of the next cycle when the neutrophil count reaches at least 1500/µl and platelets to 100000/µl.

The dose of gemcitabine in the next cycle should be reduced by 25% for all indications in cases where the previous cycle showed:

• Decrease in absolute neutrophil count < 500/µl, lasting more than 5 days;
• Decrease in absolute neutrophil count < 100/µl, lasting more than 3 days;
• Febrile neutropenia;
• Decrease in platelet count < 25,000/µl;
• The cycle was delayed for more than 1 week due to hematological toxicity.

Dosage adjustment of the drug due to non-hematological toxicity

Periodic physical examination and monitoring of liver and kidney function should be performed to detect non-hematological toxicity. The dose of the drug may be reduced in each subsequent cycle or during an already started cycle depending on the severity of toxicity of the drugs prescribed to the patient. In case of severe (grade 3 or 4) non-hematological toxicity, except for nausea/vomiting, gemcitabine therapy should be suspended or the dosage reduced depending on the decision of the attending physician. The decision to resume treatment is made by the doctor.

Method of administration

Infusion administration of gemcitabine is usually well tolerated by patients and can be performed on an outpatient basis. In case of extravasation, the infusion is stopped and administration of the drug is resumed in another vein. After gemcitabine administration, the patient should be observed for some time.

Patients with impaired liver and kidney function

Gemcitabine should be used with caution in patients with hepatic insufficiency or impaired renal function, as there is insufficient data on the use of the drug in this category of patients. Moderate renal impairment (glomerular filtration rate from 30 ml/min to 80 ml/min) does not have a noticeable effect on the pharmacokinetics of gemcitabine.

Elderly patients (>65 years)

Gemcitabine is well tolerated by patients over 65 years of age. There are no specific recommendations for changing the drug dose for this population.

Children (<18 years)

Gemcitabine is not recommended for children under 18 years of age due to insufficient information on the safety and efficacy of the drug in this population.

Recommendations for preparation of infusion solution

Only 0.9% sodium chloride solution without preservatives is used as a solvent.

To prepare the drug solution, the required amount of 0.9% sodium chloride injection solution (not less than the amount indicated in the table below) is slowly introduced into the vial and the vial is gently shaken until the contents are completely dissolved.

The resulting solution should be clear.

The maximum concentration of the reconstituted gemcitabine solution should not exceed 40 mg/ml, as incomplete dissolution of the drug is possible at higher concentrations.

The prepared gemcitabine solution containing the required dose of the drug is diluted with 0.9% sodium chloride injection solution in an amount sufficient for a 30-minute intravenous infusion before administration.

Before parenteral administration of the drug solution, it should be checked for the absence of undissolved particles and changes in the color of the solution.

The prepared drug solution is physically and chemically stable for 24 hours provided it has been stored at controlled room temperature (from 20°C (68°F) to 25°C (77°F)). From a microbiological point of view, the prepared solution should be used immediately. If the prepared solution was not used immediately and its preparation was carried out under controlled and validated aseptic conditions, the storage time is usually no more than 24 hours at room temperature (from 20°C (68°F) to 25°C (77°F)).

The prepared drug solution is intended for single use only. Any unused drug must be disposed of.

Adverse Reactions

Adverse reactions that occurred more frequently than in isolated cases are listed according to the following gradation: very common (> 10%); common (> 1% to <10%); uncommon (>0.1% to <1%); rare (> 0.01% to < 0.1%); very rare (< 0.01%).

Hematologic disorders: very common – leukopenia, neutropenia, thrombocytopenia, anemia; common – febrile neutropenia; very rare – thrombocytosis.

Gastrointestinal disorders: very common – nausea, vomiting, increased activity of hepatic transaminases (ALT, AST), ALP; common – anorexia, diarrhea, constipation, stomatitis, increased bilirubin concentration; rare – increased GGT activity.

Renal and urinary disorders: very common – mild hematuria and proteinuria; rare – renal failure, clinical signs and symptoms similar to uremic syndrome (decreased hemoglobin, increased serum creatinine, urea and/or LDH activity).

Skin and subcutaneous tissue disorders: very common – skin rash accompanied by itching, alopecia; common – skin itching, increased sweating; rare – skin ulceration, blister formation; very rare – severe skin reactions, including desquamation and bullous eruptions.

Respiratory, thoracic and mediastinal disorders: very common – dyspnea; common – cough, rhinitis; uncommon – bronchospasm, interstitial pneumonitis, pulmonary edema; rare – acute respiratory distress syndrome.

Cardiac disorders: rare – decreased blood pressure, myocardial infarction, heart failure, arrhythmia.

Nervous system disorders: common – headache, increased drowsiness, insomnia.

General disorders and administration site conditions: very common – flu-like syndrome, peripheral edema; common – increased body temperature, chills, asthenia, back pain, myalgia; uncommon – facial edema; very rare – anaphylactic reactions.

Contraindications

• Pregnancy;
• Breastfeeding period;
• Children under 18 years of age (insufficient data on efficacy and safety);
• Hypersensitivity to gemcitabine or other components of the drug.

With caution the drug should be prescribed for impaired liver and/or kidney function, bone marrow suppression (including against the background of concomitant radiation or chemotherapy), cardiovascular diseases, with metastatic liver damage, hepatitis, alcoholism, with simultaneous radiation therapy, acute infectious diseases of viral, fungal or bacterial nature (including chickenpox, herpes zoster).

Use in Pregnancy and Lactation

Contraindicated during pregnancy and lactation.

Use in Hepatic Impairment

Gemcitabine should be used with caution in patients with hepatic insufficiency, as sufficient data on the use of the drug in this category of patients are not available.

Use in Renal Impairment

Gemcitabine should be used with caution in patients with impaired renal function, as sufficient data on the use of the drug in this category of patients are not available. Moderate renal impairment (glomerular filtration rate from 30 ml/min to 80 ml/min) does not have a noticeable effect on the pharmacokinetics of gemcitabine.

Pediatric Use

Gemcitabine is not recommended for children under 18 years of age due to insufficient information on the safety and efficacy of the drug in this population.

Geriatric Use

Gemcitabine is well tolerated by patients over 65 years of age. There are no specific recommendations for changing the drug dosage for this population.

Special Precautions

Treatment with Gemtaz should be carried out only under the supervision of a physician experienced in anticancer chemotherapy.

Previous treatment with cytostatics increases the frequency and severity of leukopenia and thrombocytopenia (progressive decrease in the number of leukocytes and platelets may occur after completion of therapy). Regular monitoring of peripheral blood counts, hepatic transaminase activity and serum creatinine levels is necessary. Increasing the infusion duration and frequency of administration leads to greater toxicity.

In case of bone marrow suppression, treatment should be suspended or the dose adjusted. Women of reproductive age and men must use effective contraceptive measures.

The prepared solution should be kept at room temperature (from 15°C (59°F) to 30°C (86°F)) and used within 24 hours. It should not be frozen, as crystallization may occur. The optimal regimen for the safe administration of gemcitabine in combination with therapeutic radiotherapy regimens has not been determined to date.

Effect on ability to drive and operate machinery

During the treatment period, caution should be exercised when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

Symptoms myelodepression, anemia (excessive fatigue or weakness), leukopenia, neutropenia, manifestation of infection (chills, cough, hoarseness, pain in the side or lower back, painful or difficult urination), thrombocytopenia (bleeding, hemorrhage, black tarry stools, blood in urine and stool, ecchymoses), paresthesia, pronounced skin rash.

Treatment in case of suspected overdose, the patient should be under constant medical supervision, including blood count monitoring, and if necessary, symptomatic treatment. An antidote is unknown.

Drug Interactions

Radiation therapy

Concomitant radiation therapy (simultaneously with gemcitabine administration or with an interval of <7 days before the start of treatment): in this situation, treatment toxicity depends on many factors, including the dose of gemcitabine and the frequency of its administration, radiation dose, method of radiation therapy, the nature of the irradiated tissue and its volume. Gemcitabine has been shown to have radiosensitizing activity. In one study where patients with non-small cell lung cancer received Gemcitabine at a dose of 1000 mg/m² for 6 consecutive weeks in combination with therapeutic chest irradiation, significant toxicity was noted in the form of severe and potentially life-threatening inflammation of the mucous membranes, mainly esophagitis and pneumonitis, especially in patients with a large volume of irradiated tissue (median irradiated tissue volume 4795 cm³). Subsequent studies have shown that the combination of lower doses of gemcitabine and radiation therapy is better tolerated by patients and is characterized by a predictable toxicity profile. Thus, in one phase II study, patients with non-small cell lung cancer received radiation therapy at a dose of 60 Gy together with the administration of gemcitabine (600 mg/m² 4 times) and cisplatin (80 mg/m² 2 times) for 6 weeks. Sequential therapy (interval >7 days): according to substantial data, the administration of gemcitabine more than 7 days before the start of radiation therapy or more than 7 days after its completion is not accompanied by an increase in toxicity, except for skin damage associated with the administration of the chemotherapeutic drug after irradiation. Treatment with gemcitabine can be started 7 days after irradiation or after the resolution of all acute radiation reactions.

Both with concomitant and sequential use of gemcitabine and radiation therapy, radiation damage to the irradiated tissues (e.g., esophagitis, colitis and pneumonitis) is possible.

Other drugs that cause bone marrow suppression and radiation therapy potentiate the effect and additively suppress bone marrow function. Azathioprine, chlorambucil, glucocorticoids, cyclophosphamide, cyclosporine, mercaptopurine and other immunosuppressive agents increase the risk of infection. When administering live virus vaccines, intensification of vaccine virus replication and increased side effects are possible; when administering inactivated vaccines, suppression of antiviral antibody production is possible.

Compatibility

Compatibility studies of Gemtaz have not been conducted.

It is not recommended to mix Gemtaz with other medicinal products.

Storage Conditions

The drug should be stored in a place protected from light, out of the reach of children, at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life is 3 years.

Dispensing Status

The drug is dispensed by prescription.

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.