Gemita 1,4 g

pharmacodynamics

The antitumor preparation, the pyrimidine analog antimetabolite group, inhibits DNA synthesis. Exhibits tsiklospetsifichnost, acting on cells in the S phase and at the interface G1 and S. It is metabolized in the cell by the action of nucleoside kinases to active diphosphate and triphosphate nucleosides. Diphosphate nucleosides inhibit the action of ribonucleotide reductase (unique enzyme catalyzing the formation of deoxynucleoside triphosphates required to synthesize DNA). Triphosphate nucleosides can be incorporated into the DNA chain of (less RNA) that leads to the cessation of further DNA synthesis and programmed cell lysis (apoptosis).

Gemcitabine is also strong radiosensitizing agent, even in concentrations lower than cytotoxic.

Pharmacokinetics

C _max gemcitabine (3.2 mg / ml to 45.5 ug / ml) is achieved within 5 minutes after the end of infusion. Pharmacokinetic analysis studies with single and repeated dosing shows that V _d is largely dependent on sex. Gemcitabine plasma protein binding is negligible.

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

Gemcitabine is rapidly excreted by the kidneys mainly as an inactive metabolite 2′-deoxy-2 ‘, 2’-diftoruridina. Less than 10% imposed on / in a dose found in the urine in an unmodified form gemcitabine. Systemic clearance, which ranges from about 30 l / h / m ² to 90 liter / hour / m ² , independent of age and sex.

T _1/2 ranges from 42 minutes to 94 minutes. In compliance with the recommended dosing regimen of gemcitabine complete excretion occurs within 5-11 hours after the onset of infusion. When administered once weekly Gemcitabine does not accumulate in the body.

Combination therapy with gemcitabine and paclitaxel. When co-administration of gemcitabine and paclitaxel pharmacokinetics is not changed.

Combination therapy with gemcitabine and carboplatin. When co-administration of gemcitabine and carboplatin pharmacokinetics of gemcitabine does not change.

Impaired renal function. Renal failure mild to moderate (creatinine clearance of 30-80 ml / min) had no significant effect on the pharmacokinetics of Gemcitabine.

Active substance:
Gemcitabine

Manufacturer

Fresenius Kabi Deutschland GmbH, Germany

Composition

1 vial contains:

Active ingredients: 1594.04 mg of gemcitabine hydrochloride, which corresponds to the content of gemcitabine 1400 mg.

Excipients: Mannitol – 1400 mg Sodium acetate trihydrate – 87.5 mg Hydrochloric Acid – q.s. to adjust pH, sodium hydroxide – q.s. to adjust pH.

1400 mg vial. The carton 1 vial.

Indications

• Locally advanced or metastatic non-small cell lung cancer, as first line therapy in combination with cisplatin alone and in elderly patients with performance status of 2 (on scale ECOG-BOZ);
• unresectable, locally recurrent or metastatic breast cancer after neoadjuvant and / or adjuvant therapy with anthracyclines in the absence of contraindications to their destination in a combination therapy with paclitaxel;
• locally advanced or metastatic urothelial cancer (cancer of the bladder, renal pelvis, ureter, urethra);
• locally advanced or metastatic ovarian cancer as a monotherapy or in combination with carboplatin in patients with progressive disease after first-line therapy based on platinum-containing drugs;
• locally advanced or metastatic pancreatic cancer;
• locally advanced or metastatic cervical cancer.

Contraindications

• Pregnancy;
• during breastfeeding;
• Children under 18 years of age (lack of sufficient efficacy and safety data);
• Hypersensitivity to the active substance or to any of the excipients.

Precautions: should be administered the drug in human liver and / or kidney disease, inhibition of bone marrow hematopoiesis (including with concurrent radiotherapy or chemotherapy), cardiovascular diseases, metastatic lesions of the liver, hepatitis, alcoholism, when carried out simultaneously radiation therapy, acute infectious diseases, viral, fungal or bacterial origin (including chicken pox, shingles).

Side effects

Adverse reactions occur more frequently than in rare cases are listed according to the following gradation:

• very often (> 10%);
• often (> 1% to < 10%);
• infrequently (> 0,1% to < 1%);
• rarely (> 0,01% to < 0,1%);
• very rarely (< 0,01%)

.

From the side of hematopoiesis: very often – leukopenia, neutropenia, thrombocytopenia, and anemia; often – febrile neutropenia; very rarely – thrombocytosis.

From the digestive system: very often – nausea, vomiting, increase in liver transaminases (AST, ALT), alkaline phosphatase; often – anorexia, diarrhea, constipation, stomatitis, increased bilirubin; rarely – increased GGT activity.

From the urinary system: very often – hematuria and proteinuria is mild; rarely – renal failure, and clinical signs and symptoms similar with hemolytic-uremic syndrome (reduced hemoglobin, thrombocytopenia, increase in the concentration of bilirubin, creatinine, urea and / or LDH in blood serum).

Skin and subcutaneous tissue disorders: very often – skin rash, accompanied by itching, alopecia; often – itching, excessive sweating; rarely – skin ulcerations, blistering; very rarely – expressed skin reactions, including desquamation and bullous rashes.

The respiratory system: very often – shortness of breath; often – cough, rhinitis; rarely – bronchospasm, interstitial pneumonitis, pulmonary edema; rarely – acute respiratory distress syndrome.

Cardio-vascular system: seldom – a decrease in blood pressure, myocardial infarction, heart failure, arrhythmia.

From the nervous system: often – headache, drowsiness, insomnia.

Other: very often – flu-like symptoms, peripheral edema; often – fever, chills, asthenia, back pain, myalgia; rare – swelling of the face; very rarely – anaphylactic reactions.

How to accept, acceptance rate and dosage

Non-small cell lung cancer

In monotherapy recommended dose is 1000 mg / m ² in the 1st, 8th and 15th days of each 28-day cycle.

In combination therapy with cisplatin recommended dose – 1250 mg / m ² in the 1st and 8th day of each 21-day cycle, or 1000 mg / m2 in the 1 st, 8 th and 15 th day of each 28-day cycle. Cisplatin was administered at a dose of 70 mg / m ² in the 1st day of the cycle on the background after the water load Gemita infusion preparation.

In combination therapy with carboplatin recommended dose – 1000 mg / m ² or 1200 mg / m ² in the 1st and 8th day of each 21-day cycle. Carboplatin is administered at a dose AUC 5,0 mg / ml / min 1st cycle day after drug infusion Gemita.

Mammary cancer

In combination therapy as therapy 1st line with the progression of the disease after neoadjuvant therapy including an anthracycline, a recommended dose – 1250 mg / m ² in the 1st and 8th days in combination with paclitaxel, which is introduced Gemita after administration at a dose of 175 mg / m ² in the 1st day of each 21-day cycle / drip for approximately 3 hours.

urothelial cancer

In monotherapy recommended dose is 1250 mg / m ² in the 1st, 8th and 15th days of each 28-day cycle.

In combination therapy recommended dose -1000 mg / m ² in the 1st, 8th and 15th days, in combination with cisplatin, which is administered in a dose of 70 mg / m ^{2 < / sup> immediately after infusion Gemita in the 1st or the 2nd day of each 28-day cycle.}

ovarian cancer

In monotherapy recommended dose – 800-1250 mg / m ² in the 1st, 8th and 15th days of each 28-day cycle.

Pancreas cancer

In monotherapy recommended dose – 1000 mg / m ² 1 time per week for 7 weeks, followed by one week apart. Then the drug is administered in the 1st, 8th and 15th days of each 28-day cycle.

Cervical cancer (locally advanced or metastatic)

Combination therapy: in locally advanced cancer (neoadjuvant) and metastatic cancer, gemcitabine is administered at a dose of 1250 mg / m ² in the 1st and 8th days of each 21-day cycle. Cisplatin is administered after administration Gemita 70 mg / m ² in the 1st day of the cycle on the background of overhydration.

In locally advanced cancer with simultaneous radiotherapy Gemita drug is administered 1 time per week for 6 weeks in a dose of 125 mg / m ² , followed by (directly after drug administration Gemita) cisplatin at a dose of 40 mg / m ² for 1-2 hours prior to radiotherapy. Radiation therapy is carried out for 28 fractions in single focal dose 1.8 g, 5 days per week to a total focal dose was 50.4

Changing the dose due to the phenomenon of hematological toxicity

Start the treatment cycle

Regardless of the readings before each administration of the drug to estimate the number of platelets and granulocytes. The condition for initiation of treatment absolute neutrophil count is at least 1500 / ml and the platelet count of at least 100,000 / L.

In the case of hematologic toxicity during the treatment cycle Gemita dose preparation may be reduced or delayed its introduction in accordance with the following guidelines.

Modification Gemita drug dose used in monotherapy or in combination with cisplatin in the treatment of bladder cancer, non-small cell lung cancer and pancreatic cancer.

* – When the number of neutrophils to 500 / l and platelets to 50,000 / mm Gemita administration of the drug can be continued in the cycle.

Modification Gemita dose formulation employed in combination with paclitaxel in the treatment of breast cancer.

* – Treatment in the cycle is not resumed. Another Gemita drug administration is carried out 1 day the next cycle when the minimum number of neutrophils and 1500 / l and 100,000 platelets / .mu.l.

Modification Gemita dose formulation employed in combination with carboplatin in the treatment of ovarian cancer.

* – Treatment in the cycle is not resumed. Another Gemita drug administration is carried out 1 day the next cycle when the minimum number of neutrophils and 1500 / l and 100,000 platelets / .mu.l.

Gemita dose at the next cycle should be reduced by 25% for all indications in cases where the observed in the previous cycle:

• decrease in absolute neutrophil count < 500 / L, continuing for more than 5 days;
• decrease in absolute neutrophil count < 100 / ul, the continued over 3 days;
• febrile neutropenia; – reduction of platelet count < 25,000 / ul;
• cycle was delayed by more than 1 week due to hematological toxicity.

Route of administration

Infusion administration Gemita drug is usually well tolerated by patients and can be conducted in an outpatient setting. If extravasation infusion was stopped and restarted administering the drug in a different vein. After the introduction of the drug Gemita patient should be observed for some time.

Gemita apply the drug in patients with hepatic failure or impaired renal function with caution, because insufficient data on the use of the drug in this category of patients there. Renal failure mild or moderate (glomerular filtration rate from 30 ml / min to 80 mL / minute) has no marked effect on the pharmacokinetics of Gemcitabine.

Gemita The drug is well tolerated by elderly patients older than 65 years. Specific recommendations for changing the dose for this population are not available.

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

Rules of the solution for infusion

As the solvent used only 0.9% sodium chloride solution without preservatives.

To prepare the solution for infusion vial contents were dissolved 200 mg of not less than 5 ml, 1000 mg – not less than 25 ml, and 1400 mg – not less than 35 ml 0.9% sodium chloride solution for injection. Each vial is gently agitated until complete dissolution of the lyophilizate. The resulting solution should be clear.

The maximum concentration of gemcitabine should not exceed 40 mg / ml. The solutions were prepared at a concentration higher than 40 mg / ml, can be accompanied by incomplete dissolution.

Gemita prepared solution preparation containing the desired dose of the drug, before administration diluted with 0.9% sodium chloride solution for injection in a quantity sufficient for 30 minutes in / infusion.

Prior to parenteral administration must visually monitor the prepared solution for mechanical impurities and color variation.

Cooked Gemita drug solution is stable from a physical and chemical point of view for 24 hours under the condition that it was stored at controlled room temperature (from 20 ° C to 25 ° C). From the microbiological point of view, the prepared solution should be used immediately. In the case where the prepared solution was not used immediately and its preparation was carried out in a controlled and validated aseptic conditions, the retention time is typically no more than 24 hours at room temperature (20 ° to 25 ° C).

Storage conditions

At temperatures above 25 ° C (not frozen)

Active substance

Gemcitabine

Interaction

Radiation therapy

Concomitant radiation therapy (simultaneously with administration of the drug Gemita or interval < 7 days before the treatment): in this situation treatment toxicity depends on many factors including the dose of gemcitabine and its frequency of administration, the dose of radiation, a method of radiation therapy, the nature of the irradiated tissue and its volume. It was shown that gemcitabine has radiosensitizing activity. In one study where patients with NSCLC was prepared gemcitabine 1000 mg / m ² for 6 consecutive weeks in combination with therapeutic radiation to the chest area was marked significant toxicity in the form of severe and potentially life-threatening inflammation of mucous membranes, mainly esophagitis and pneumonitis, especially in patients with a large volume of tissue irradiation (median volume of irradiated tissue 4795 cm ³ ). Subsequent studies have shown that the combination of lower doses of gemcitabine and radiation therapy is better tolerated by patients and is characterized by predictable toxicity profile. Thus, in one of the II-phase studies patients with non-small cell radiotherapy lung conducted cancer in a dose of 60 Gy in conjunction with administering gemcitabine (600 mg / m ² 4 times) and cisplatin (80 mg / m ² 2-fold) for 6 weeks.

Sequential therapy (break > 7 days): from existing data, gemcitabine more than 7 days prior to the radiotherapy, or more than 7 days after its completion is not accompanied by an increase in toxicity, with the exception of skin lesions associated with the administration of chemotherapy after irradiation . gemcitabine treatment can be initiated 7 days after exposure or after resolution of acute radiation reactions.

As with concomitant or sequential use of gemcitabine and radiation therapy may radiation injury irradiated tissue (e.g., esophagitis, colitis and pneumonia).

Other interactions

While the use of live attenuated vaccines is possible intensification of replication of vaccine virus, increasing its side / adverse effects and / or reduce the production of antibodies in the patient’s body in response to the vaccine.

Immunosuppressants (including azathioprine, chlorambucil, corticosteroids, cyclophosphamide, cyclosporine, mercaptopurine) increase the risk of infections.

Compatibility studies have not been conducted Gemita drug. Mix preparation Gemita with other drugs is not recommended.

Special conditions

Treatment with Gemita can be carried out only under the supervision of a physician with experience in cancer chemotherapy.

Before each administration of the drug to be determined Gemita leukocytic formula and the number of blood platelets. When signs of bone marrow function oppression caused by the drug, it is necessary to suspend the treatment or adjust the dose.

It is necessary to carry out regular inspection of the patient and evaluate renal and hepatic function.

Introduction Gemita drug metastases in the liver, hepatitis and alcoholism in history, as well as in liver cirrhosis increases the risk of liver failure.

When signs of adverse events of the respiratory system (e.g., pulmonary edema, pneumonitis or interstitial respiratory distress syndrome in adults) patients Gemita drug treatment should be discontinued and prescribe appropriate therapy.

At the first signs of microangiopathic hemolytic anemia, such as the rapid decrease in hemoglobin with accompanying thrombocytopenia, increased serum bilirubin, creatinine, nitrogen, urea or increased LDH activity, the preparation should be discontinued. Increasing the duration and frequency of administrations infusion leads to an increase in toxicity.

Depending on the degree of toxicity the dose may be reduced during each cycle or to start a new cycle steps.

During treatment and for 6 months after the end of therapy with Gemita should use reliable methods of contraception. Men receiving drug Gemita recommended resort to semen cryopreservation prior to treatment because of the risk of sterility caused by the use of this drug.

Gemcitabine can be administered after starting the permission of acute radiation reactions or not earlier than 7 days after the radiotherapy.

Gemcitabine monotherapy or in combination with other anticancer agents has activity in advanced small cell lung cancer, testicular cancer progressing cancer and biliary ducts.

Effects on ability to drive vehicles and other machines that require high concentration of attention

Data on the effect of drug therapy Gemita on ability to drive and work with the absence of a mechanism, however, some side effects of the drug, such as increased drowsiness, may adversely affect driving ability and the performance of potentially hazardous activities that require attention increased concentration and psychomotor speed reactions, which requires compliance with caution.

Pregnancy and lactation

Do not use this drug during pregnancy and lactation (breastfeeding).

Overdose

The antidote to gemcitabine is unknown. Gemita when administered in doses up to 5700 mg / m ² / drip for 30 minutes every 2 weeks for toxicity treatment remained acceptable. In case of suspected overdose gemcitabine should be monitored and set the degree of cytopenia maintenance therapy if necessary.