Gemcitar lyophilizate 200 mg

Antitumor agent. It has cytostatic action, which is associated with inhibition of DNA synthesis. In the cell it is metabolized to active diphosphate and triphosphate nucleosides. Diphosphate nucleosides inhibit the action of ribonucleotide reductase, with the participation of which deoxynucleoside triphosphates necessary for DNA synthesis are formed in the cell, which leads 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, resulting in complete inhibition of further DNA synthesis and programmed cell death.

Indications

– Locally advanced or metastatic non-small cell lung cancer as first-line therapy in combination with cisplatin and carboplatin and as monotherapy in elderly patients with functional status equal to 2.

– Nonresectable, locally recurrent or metastatic breast cancer as part of combination therapy with paclitaxel after neoadjuvant and/or adjuvant therapy including anthracyclines, if there are no contraindications to their administration.

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

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

– Locally advanced or metastatic pancreatic cancer.

– Locally advanced or metastatic cervical cancer.

– Biliary tract cancer.

Gemcitabine has been shown to be effective in advanced small cell lung cancer and advanced refractory testicular cancer.

Active ingredient

Composition

How to take, the dosage

Gemcitabine is given intravenously by capsule for 30 minutes.

Before each administration of gemcitabine, the number of platelets, white blood cells and granulocytes in the blood should be monitored. If there are signs of depressed bone marrow function caused by the drug, treatment should be stopped or the dose adjusted.

Non-small cell lung cancer (locally advanced or metastatic), first-line therapy

Monotherapy

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

Combination therapy with cisplatin

The recommended dose of 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 the first day of the cycle after gemcitabine infusion against a background of hyperhydration.
Combination therapy with carboplatin: the recommended dose of the drug is 1000 mg/m2 or 1250 mg/m2 on days 1 and 8 of each 21-day cycle. Carboplatin is administered at an AUC (area under the concentration-time curve) of 5.0 mg/mL/min on day 1 of the cycle after gemcitabine infusion.

Breast cancer (unresectable, locally recurrent or metastatic)

Urothelial cancer (bladder cancer (locally advanced, metastatic and superficial), renal pelvis, ureter, and urethra)

Monotherapy

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

Combination therapy with cisplatin

The recommended dose of 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. Clinical studies have shown that cisplatin doses of 100 mg/m2 show greater myelosuppression.

Epithelial ovarian cancer (locally advanced or metastatic, resistant to platinum derivatives)

Monotherapy

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

Combination therapy with carboplatin

The recommended dose of drug is 1000 mg/m2 on days 1 and 8 in combination with carboplatin at an AUC of 4.0 mg/mL/min, which is administered immediately after the gemcitabine infusion on day 1 of each 21-day cycle.

Pancreatic cancer (locally advanced or metastatic, including those resistant to fluorouracil therapy)

Monotherapy

The recommended dose of drug is 1000 mg/m2 once weekly for 7 weeks, followed by a one-week pause. The drug is then administered on days 1, 8, and 15 of each 28-day cycle.

Cervical cancer (locally advanced or metastatic)

Combination therapy with cisplatin

Biliary tract cancer

Combination therapy with cisplatin

Dose adjustment

If hematologic toxicity develops, the dose of Gemcitabine® may be reduced or its administration delayed according to the following regimens:

A. Cycle gemcitabine dose adjustment in urothelial cancer, non-small cell lung cancer, pancreatic cancer in monotherapy or in combination with cisplatin

Absolute granulocyte count

(x 109/L)

Platelet count

(x 109/l)

% of previous dose

>1

and

>100

100

0.5-1

or

50-100

75

< 0.5

or

< 50

Postpone administration

B. Correcting the dose of gemcitabine within a cycle for breast cancer in combination with paclitaxel

Absolute granulocyte count

(x 109/L)

Platelet count

(x 109/l)

% of previous dose

≥1.2

and

≥75

100

1-< 1,2

or

50-75

75

0.7-< 1

and

≥50

50

< 0.7

or

< 50

delay administration

B. Cycle gemcitabine dose adjustment for ovarian cancer in combination with carboplatin

Absolute granulocyte count

(x 109/L)

Platelet count

(x 109/l)

% of the previous dose

>1.5

and

≥100

100/p>

1-1.5

or

75-100

50

< 1

or

< 75

Postpone administration

For non-hematologic toxicity, regular patient evaluation and monitoring of hepatic and renal function should be performed. Depending on the degree of toxicity, the dose may be reduced during each cycle or with the start of a new cycle in steps. Administration of the drug should be delayed until, in the opinion of the physician, the toxicity has resolved.

Particular patient groups

Elderly patients

There is no data to suggest that dose adjustments are necessary in elderly patients.

Patients with impaired hepatic or renal function

The use of gemcitabine in patients with hepatic impairment or impaired renal function should be used with caution, as there are insufficient data on the use of the drug in this patient population.

Mild to moderate renal insufficiency (glomerular filtration rate from 30 ml/min to 80 ml/min) has no appreciable effect on the pharmacokinetics of gemcitabine.

Children

Hemcitabine has been studied in limited phase I and II studies in children with different types of neoplasms. Data from these studies are insufficient to prove the efficacy and safety of gemcitabine in children.

Interaction

Radiation therapy

Concomitant use (coadministration or less than 7 days apart): the toxicity associated with this multimodality treatment depends on many different factors: gemcitabine dose, frequency of gemcitabine administration, radiation therapy dose, radiation therapy planning technique, type and volume of irradiated tissue.

Preclinical and clinical studies have shown that gemcitabine has radiosensitizing effects. In the only study in which gemcitabine was administered at a dose of 1000 mg/m2. for 6 weeks concurrently with therapeutic chest irradiation in patients with non-small cell lung cancer, significant toxicity in the form of severe and potentially life-threatening mucosal inflammation, mainly esophagitis; and pneumonitis, especially in patients with large tissue volume irradiation (median volume irradiation 4795 cm3) was documented.

Later studies (phase II studies in non-small cell lung cancer) suggest that gemcitabine administration at lower doses with concomitant radiation therapy with predicted toxicity is appropriate. Radiation therapy to the chest area (SOD 66 Gy) was performed concomitantly with chemotherapy with gemcitabine at a dose of 600 mg/m2 (4 injections) and cisplatin at a dose of 80 mg/m2 (2 injections) for 6 weeks.

Few phase I and II studies have shown that gemcitabine monotherapy (up to 300 mg/m2/week) in non-small cell lung cancer and pancreatic cancer is appropriate in conjunction with radiotherapy.

The optimal regimen for the safe administration of gemcitabine with therapeutic doses of radiation therapy has not yet been established for all tumor types.

Consecutive use (interval greater than 7 days): Except for a radiation reaction when gemcitabine is administered more than 7 days before or after radiotherapy, no increase in toxicity has been reported. These data suggest that gemcitabine can be administered one week after radiation therapy or after the acute effects of radiation therapy have resolved.

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

Others:

The co-administration with live yellow fever vaccines and other live vaccines is not recommended because of the risk of systemic disease with possible lethal outcome, especially in immunosuppressed patients.

Special Instructions

Treatment with gemcitabine should only be performed under the supervision of a physician experienced in the use of anti-tumor chemotherapy.

Hematological toxicity

Hemcitabine may inhibit bone marrow function, manifested by leukopenia, thrombocytopenia or anemia. The number of platelets, leukocytes and granulocytes in the blood should be determined before each drug administration. In case of signs of depression of bone marrow function the treatment should be stopped or the dose should be adjusted.

Hepatic and renal function

The patient should be regularly evaluated and renal and hepatic function evaluated. Administration of gemcitabine for liver metastases, a history of hepatitis and alcoholism, and cirrhosis increases the risk of liver failure.

Contraindications

– Hypersensitivity to gemcitabine or other components of the drug;

– pregnancy and lactation;

– Childhood under 18 years of age (lack of sufficient experience of use)

Side effects

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

The blood and lymphatic system: very often – anemia, leukopenia and thrombocytopenia; often – febrile neutropenia; very rarely – thrombocytosis.

The immune system: very rare – anaphylactic reaction.

Metabolism and nutrition: often – anorexia.

Nervous system disorders: frequent – headache, insomnia, somnolence; infrequent – cerebral circulatory disorders; very rare – reversible posterior encephalopathy syndrome.

Cardiac: infrequent – heart failure; arrhythmia, predominantly supraventricular; rarely – myocardial infarction.

Vascular disorders: very common – edema, peripheral edema; rare – decreased blood pressure, peripheral vasculitis, gangrene; very rare – syndrome of increased capillary permeability.

Respiratory system: very common – shortness of breath; common – cough, rhinitis, infrequent – bronchospasm, interstitial pneumonitis; rare – pulmonary edema, adult respiratory distress syndrome.

Gastrointestinal system disorders: very common – nausea, vomiting, increased activity of “liver” enzymes aspartate aminotransferase (ACT), alanine aminotransferase (ALT) and alkaline phosphatase; common – diarrhea, stomatitis, oral ulcers, constipation, increased bilirubin concentration, infrequent – severe hepatotoxicity, including liver failure, in some cases with lethal outcome; rare – increased concentration of gammaglutamyltransferase (GGT); very rare – ischemic colitis.

Skin and skin appendages: very common – mild allergic skin rash accompanied by itching; alopecia (usually minimal hair loss); often itching, sweating; rare – ulcers, vesicle formation, peeling, severe skin reactions, including desquamation and bullous skin lesions; very rare – toxic epidermal necrolysis, Stevens-Johnson syndrome.

Recreational and urinary tract disorders: very common – mild proteinuria and hematuria, infrequent – renal failure; rare – increased concentration of creatinine, urea and lactate dehydrogenase (LDH) in hemolytic-uremic syndrome.

Skeletal-muscular system and connective tissue: often – back pain, myalgia.

Others: very often – flu-like syndrome. There have also been recorded cases of malaise, sweating; often – increase in body temperature, asthenia, chills; rarely – reactions at the injection site of mostly mild degree.

Hypersensitivity:

Anaphylactoid reactions have been reported very rarely.

Radiation toxicity has rarely been reported (see “Interaction with other therapies”).

The use of gemcitabine in combination with paclitaxel in breast cancer

Severe Grade III adverse events

Hematological toxicity:

Anemia 5.7%, thrombocytopenia 5.3%, neutropenia 31.3%.

Nonhematologic toxicity:

febrile neutropenia – 4.6%, increased fatigue – 5.7%, diarrhea – 3.1%, motor neuropathy – 2.3%, sensory neuropathy – 5.3%.

Grade IV adverse events

Hematologic toxicity:

Anemia – 1.1%, thrombocytopenia – 0.4%, neutropenia – 17.2% (grade IV neutropenia lasting more than 7 days was reported in 12.6% of patients).

Non-hematologic toxicity:

febrile neutropenia – 0.4%, increased fatigue – 0.8%, motor neuropathy – 0.4%, sensory neuropathy – 0.4%.

The use of gemcitabine in combination with cisplatin in bladder cancer

Severe Grade III adverse events

Hematological toxicity:

Anemia 24%, thrombocytopenia 29%.

Non-hematologic toxicity:

Nausea and vomiting – 22%, diarrhea – 3%, infection – 2%, stomatitis – 1%.

Unwanted phenomena of severity IV

Hematologic toxicity:

anemia – 4%, thrombocytopenia – 29%.

Non-hematologic toxicity:

Infection – 1%.

The use of gemcitabine in combination with carboplatin in ovarian cancer

Adverse events of grade III severity

Hematologic toxicity:

Anemia 22.3%, neutropenia 41.7%, thrombocytopenia 30.3%, leukopenia 48.0%

Nonhematologic toxicity:

bleeding 1.8%, febrile neutropenia 1.1%.

Grade IV adverse events

Hematologic toxicity:

anemia – 5.1%, neutropenia – 28.6%, thrombocytopenia – 4.6%, leukopenia – 5.1%.

Non-hematologic toxicity:

infection without neutropenia – 0.6%

Overdose

Clinically tolerable toxicity was observed with single doses up to 5.7 g/m2 intravenously for 30 minutes every 2 weeks.

Symptoms: myelosuppression, paresthesias, marked skin rash, hemorrhagic syndrome.

Treatment: there is no specific antidote. If overdose is suspected the patient should be under constant medical control, including complete blood count with determination of leukocyte formula; if necessary symptomatic treatment is carried out.

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