Gemzar lyophilizate solution concentrate for infusion, 200mg vial 1pc

Composition

1 bottle contains:

Active ingredients:

gemcitabine hydrochloride 228 mg, which corresponds to the content of gemcitabine 200 mg.

Auxiliary substances:

mannitol-200 mg,

sodium acetate-12.5 mg

Pharmacological action

Pharmacodynamics

Antitumor drug, an antimetabolite of the pyrimidine analog group. The drug exhibits cyclospecificity, acting on cells in phases S (replication phase) and G1/S (the interval between the initial growth phase and the replication phase).

Gemcitabine is metabolized within the cell by nucleoside kinases to form active diphosphate and triphosphate nucleosides. Diphosphate nucleosides inhibit ribonucleotide reductase, which acts as the sole catalyst for reactions leading to the formation of deoxynucleoside triphosphates necessary for DNA synthesis. Triphosphate nucleosides actively compete with deoxycytidine triphosphate for incorporation into DNA and RNA molecules. Once the intracellular metabolites of gemcitabine are incorporated into the DNA strand, another additional nucleotide is added to its growing strands, which leads to complete inhibition of further DNA synthesis and programmed cell death, known as apoptosis.

Pharmacokinetics

Distribution

Binding to plasma proteins is insignificant.

Elimination

T1 / 2 ranges from 32 to 94 min. Gemcitabine is rapidly eliminated from the body by the kidneys, mainly in the form of an inactive metabolite of 2′ – deoxy-2′,2′ – difluoruridine. Less than 10% of the intravenous dose is found unchanged in the urine.

Systemic clearance ranges from 30 to 90 l / h / m2.

Pharmacokinetics in special clinical cases

Analysis of pharmacokinetic studies with single and multiple drug use shows that Vd is largely gender-dependent.

Systemic clearance, which ranges from approximately 30 l / h / m2 to 90 l / h/m2, depends on gender and age.

Indications

• Locally common or metastatic non-small cell lung cancer as first-line therapy in combination with cisplatin or carboplatin, and also as monotherapy in elderly patients with performance status of 2;
• unresectable, mestorozhdenii or metastatic breast cancer in combination therapy with paclitaxel after neoadjuvant and/or adjuvant therapy with the inclusion of anthracyclines in the absence of contraindications to their destination;
• locally common or metastatic urothelial carcinoma (bladder cancer, renal pelvis, ureter, urethra);
• locally advanced or metastatic spread of epithelial ovarian cancer as monotherapy or in combination with carboplatin in patients with disease progression after the first-line therapy on the basis of platinum derivatives;
• locally common or metastatic pancreatic cancer;
• locally advanced or widespread metastatic cervical cancer;
• cancer of the biliary tract.

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

Use during pregnancy and lactation

The drug is contraindicated during pregnancy and lactation (breastfeeding).

Contraindications

• Age up to 18 years;
• pregnancy;
• lactation (breastfeeding);
• hypersensitivity to gemcitabine or other components of the drug.

With caution: prescribe the drug in case of impaired liver and/or kidney function, suppression of bone marrow hematopoiesis (including on the background of concomitant radiation or chemotherapy), acute infectious diseases of a viral, fungal or bacterial nature.

Side effects

Side effects that occurred more frequently than in isolated cases are listed in accordance with the following gradation: :

• very often (≥10%);
• often (≥1%, < 10%);
• infrequently (≥0,1%, < 1%);
• rarely (≥0,01%, < 0,1%);
• very rare (

From the hematopoietic system: very often – anemia, leukopenia, thrombocytopenia; often-febrile neutropenia; very rarely-thrombocytosis.

From the side of metabolism: often – anorexia.

From the nervous system: often-headache, sleep disturbance, drowsiness.

From the cardiovascular system: very often-edema, peripheral edema; infrequently-heart failure, arrhythmia, mainly supraventricular; rarely-myocardial infarction, decreased blood pressure.

From the respiratory system: very often – shortness of breath; often – cough, rhinitis; infrequently – bronchospasm.

From the digestive system: very often – liver dysfunction (usually mild, rarely requiring discontinuation of treatment), nausea, vomiting; often-diarrhea, stomatitis, constipation.

From the skin and subcutaneous tissues: very often – mild skin rashes accompanied by itching, alopecia (usually minimal hair loss); often-itching, sweating; rarely-ulcers, vesicle formation.

From the urinary system: very often-mild proteinuria and hematuria.

From the musculoskeletal system: often-back pain, myalgia.

Allergic reactions: very rarely-anaphylactoid reactions, anaphylactic reaction.

Other: very often – flu-like syndrome (fever, headache, chills, asthenia, malaise); rarely – injection site reactions. Fever and asthenia are often reported as separate symptoms. Radiation toxicity was rarely reported.

Post-marketing data

From the cardiovascular system: infrequently-heart failure, arrhythmia, mainly supraventricular; rarely-gangrene and peripheral vasculitis; very rarely-increased capillary permeability syndrome.

From the respiratory system: infrequently-interstitial pneumonitis; rarely-adult respiratory distress syndrome, pulmonary edema. Discontinuation of gemcitabine therapy should be considered if these effects occur. Early maintenance therapy may improve the situation.

From the digestive system: very rarely – ischemic colitis.

Skin and subcutaneous tissue disorders: rarely-severe skin reactions, including desquamation and bullous skin lesions.

From the urinary system: infrequently-hemolytic-uremic syndrome. At the first sign of any signs of microangiopathic hemolytic anemia (for example, a sharp decrease in hemoglobin with concomitant thrombocytopenia, an increase in bilirubin, serum creatinine, urea or LDH), gemcitabine therapy should be stopped immediately. Renal failure may be irreversible even after discontinuation of therapy and dialysis may be required.

From the liver and biliary tract: very often-increased activity of liver enzymes: ACT, ALT, ALP; often-increased bilirubin concentration; infrequently-severe hepatotoxicity, including liver failure; rarely-increased GGT activity.

Other: very rare – Lyell’s syndrome, Stevens-Johnson syndrome; radiation reactions have been reported.

Interaction

Radiation therapy

Simultaneous use (combined or at intervals of less than 7 days): The toxicity associated with such multimodal treatment depends on many different factors: the dose of gemcitabine, the frequency of gemcitabine use, the dose of radiation therapy, the technique of planning radiation therapy, and the type and volume of tissue to be irradiated.

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

Later studies (phase II studies in non-small cell lung cancer) indicate the feasibility of introducing gemcitabine in lower doses with concomitant radiation therapy with predicted toxicity. Radiation therapy for the chest area (SOD 66 Gy) was performed simultaneously 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. Several phase I and II studies have shown that in non-small cell lung cancer and pancreatic cancer, gemcitabine monotherapy (at a dose of up to 300 mg/m2/week) is more appropriate in parallel with radiation therapy. The optimal regimen for safe use of gemcitabine with therapeutic doses of radiation therapy has not yet been established for all types of neoplasms.

Sequential use (interval of more than 7 days): in addition to the radiation reaction when gemcitabine was administered more than 7 days before or after radiation therapy, no increase in toxicity was recorded. These data suggest that gemcitabine can be administered one week after radiation therapy or after the acute effects of radiation therapy have been eliminated. Both concomitant and sequential use of gemcitabine with radiation therapy has been associated with radiation-induced tissue damage (e. g., esophagitis, colitis, and pneumonitis).

Other services

Concomitant use with live yellow fever vaccines and other live vaccines is not recommended, due to the risk of systemic disease with a possible fatal outcome, especially in patients with immunosuppression.

How to take it, course of use and dosage

Gemzar® is administered intravenously for 30 minutes.

Before each use of gemcitabine, it is necessary to monitor the number of platelets, white blood cells and granulocytes in the blood. If there are signs of bone marrow suppression caused by the drug, it is necessary to suspend treatment or adjust the dose.

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

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 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 after gemcitabine infusion on the background of hyperhydration.

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 an AUC of 5.0 mg / ml / min on day 1 of the cycle after gemcitabine infusion.

Breast cancer (unresectable, locally recurrent, or metastatic)

Combination therapy with paclitaxel: as first-line therapy for disease progression after neoadjuvant and / or adjuvant therapy, including anthracyclines in the absence of contraindications to them. Paclitaxel is administered at a dose of 175 mg/m2 intravenously for 3 hours on day 1 of a 21-day cycle, followed by gemcitabine. The recommended dose of the drug is 1250 mg / m2 on days 1 and 8 of each 21-day cycle.

Before starting combination therapy (gemcitabine+paclitaxel), the absolute number of granulocytes in the blood should be at least 1500/µl.

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

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

Combination therapy with cisplatin: 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 2 of each 28-day cycle. Clinical studies have shown that more pronounced myelosuppression is observed at a cisplatin dose of 100 mg/m2.

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

Monotherapy: the recommended dose of the 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 the drug is 1000 mg/m2 on days 1 and 8 in combination with carboplatin at the rate of AUC of 4 mg/ml/min, which is administered immediately after gemcitabine infusion on day 1 of each 21 – day cycle.

Pancreatic cancer (locally advanced or metastatic, including those resistant to 5-fluorouracil therapy)

Monotherapy: the recommended dose of the drug is 1000 mg / m2 once a week for 7 weeks, followed by a one-week break. 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: for locally advanced cancer, sequential chemoradiotherapy (neoadjuvant) and metastatic cancer, cisplatin is administered at a dose of 70 mg / m2 on day 1 of the cycle against the background of hyperhydration, followed by gemcitabine use. Gemcitabine is administered at a dose of 1250 mg / m2 on days 1 and 8 of each 21-day cycle.

In locally advanced cancer with concomitant chemoradiotherapy, cisplatin is administered at a dose of 40 mg / m2, followed (immediately after cisplatin use)by gemcitabine. Gemcitabine is administered once a week 1-2 hours before the start of radiation therapy at a dose of 125 mg / m2.

Biliary tract cancer

Combination therapy with cisplatin: cisplatin is administered at a dose of 70 mg / m2 on day 1 of the cycle against the background of hyperhydration, followed by gemcitabine. Gemcitabine is administered at a dose of 1250 mg / m2 on days 1 and 8 of each 21-day cycle.

Dose adjustment

In case of development of hematological toxicity, the dose of gemcitabine may be reduced or its use postponed in accordance with the following schemes:

A. Dose adjustment of gemcitabine as part of a cycle for urothelial cancer, non-small cell lung cancer, pancreatic cancer as monotherapy or in combination with cisplatin.

Absolute number of granulocytes (in 1 µl)

Platelet count (in 1 µl)

% of the previous dose

> 1000>

and

> 100 000>

100

500-1000

or

50 000-100 000

75

< 500

or

< 50 000

Postpone introduction

B. Dose adjustment of gemcitabine in a cycle for breast cancer in combination with paclitaxel.

Absolute number of granulocytes (in 1 µl)

Platelet count (in 1 µl)

% of the previous dose

≥1200

and

>75 000>

100

1000 – < 1200

or

50 000-75 000

75

700-

and

≥50,000

50

V. Correction of the gemcitabine dose during the ovarian cancer cycle in combination with carboplatin.

Absolute number of granulocytes (in 1 µl)

Platelet count (in 1 µl)

% of the previous dose

>1500>

and

≥100 000

100

1000-1500

or

75 000 -100 000

50

or

Postpone introduction

To detect non-hematological toxicity, it is necessary to conduct a regular examination of the patient and monitor liver and kidney function. Depending on the degree of toxicity, the dose can be reduced during each cycle or with the start of a new cycle in stages.

use of the drug should be delayed until, in the opinion of the doctor, the toxicity is resolved.

Special patient groups

There is no evidence to suggest that dose adjustment is required in elderly patients.

Gemcitabine should be used with caution in patients with hepatic insufficiency or impaired renal function, since there are no sufficient data on the use of the drug in this category of patients. Renal insufficiency of mild or moderate severity (GFR from 30 ml / min to 80 ml / min) does not significantly affect the pharmacokinetics of gemcitabine.

Gemcitabine has been studied in limited phase 1 and 2 trials in children with different types of neoplasms. Data from these studies are insufficient to prove the efficacy and safety of gemcitabine in children.

Rules for preparing the solution for infusions

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

To prepare the infusion solution, the contents of the 200 mg vial are dissolved in at least 5 ml, and 1 g-in at least 25 ml of 0.9% sodium chloride solution for injection. Each bottle is gently shaken until the lyophilizate is completely dissolved. The resulting solution should be transparent.

The maximum concentration of gemcitabine should not exceed 40 mg / ml. In solutions prepared with a concentration of more than 40 mg/ml, incomplete dissolution is possible.

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

Before parenteral use, it is necessary to visually monitor the prepared solution for the presence of mechanical impurities and discoloration.

Overdose

Treatment: No known antidote.

Clinically acceptable toxicity was observed when single doses of up to 5.7 g/m2 were administered intravenously for 30 minutes every 2 weeks.

If an overdose is suspected, the patient should be under constant medical supervision, including counting the blood formula.

If necessary, carry out symptomatic treatment.

Special instructions

Treatment with gemcitabine should only be carried out under the supervision of a doctor who has experience in the use of antitumor chemotherapy.

Before each use of gemcitabine, it is necessary to monitor the number of platelets, white blood cells and granulocytes in the blood. If there are signs of bone marrow suppression caused by the drug, it is necessary to suspend treatment or adjust the dose.

It is necessary to conduct a regular examination of the patient and assess the function of the kidneys and liver. The use of gemcitabine in patients with liver metastases, hepatitis and alcoholism in the anamnesis, as well as in patients with cirrhosis of the liver increases the risk of developing liver failure.

An increase in the duration of the infusion and the frequency of use leads to an increase in toxicity.

Gemcitabine may inhibit bone marrow activity, such as leukopenia, thrombocytopenia, or anemia.

Increased capillary permeability syndrome with potentially serious consequences has been observed in patients treated with gemcitabine alone or in combination with other chemotherapeutic agents. If capillary permeability syndrome develops during therapy, gemcitabine treatment should be discontinued and the necessary measures taken. According to some literature data, the syndrome of increased capillary permeability has been associated with adult respiratory distress syndrome.

Depending on the degree of toxicity, the dose can be reduced during each cycle or with the start of a new cycle in stages.

Influence on the ability to drive vehicles and other mechanisms that require increased concentration of attention

Studies of the effect of gemcitabine on the ability to drive motor vehicles and other mechanisms have not been conducted. However, gemcitabine is known to cause mild to moderate drowsiness, especially when combined with alcohol consumption.

Patients should be cautioned against operating machinery when they feel drowsy.

Form of production

Lyophilizate for preparation of solution for infusions.

Storage conditions

At a temperature of 15-30 °C

Shelf life

3 years

Active ingredient

Gemcitabine

Conditions of release from pharmacies

By prescription

Dosage form

solution for infusions

Purpose

For adults as directed by your doctor

Indications

Cancer, Breast Cancer