Composition, form of production and packaging
Lyophilizate for the preparation of a solution for infusions in the form of a compact mass or powder of white or almost white color.
1 f.
gemcitabine hydrochloride 227.7 mg,
which corresponds to the content of gemcitabine 200 mg
Excipients: mannitol - 200 mg, sodium acetate - 12.5 mg, hydrochloric acid - qs to pH 2.7-3.3 and sodium hydroxide - to pH 2.7-3.3.
Vials with a capacity of 10 ml (1) - packs cardboard.
Lyophilizate for the preparation of a solution for infusions in the form of a compact mass or powder of white or almost white color.
1 f.
gemcitabine hydrochloride 1138.5 mg,
which corresponds to the content of gemcitabine 1000 mg
Excipients: mannitol 1000 mg, sodium acetate 62.5 mg, hydrochloric acid qs to pH 2.7-3.3 and sodium hydroxide qs to pH 2.7-3.3.
Glass bottles with a capacity of 50 ml (1) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2014.
PHARMACHOLOGIC EFFECT
Antitumor drug, antimetabolite group of pyrimidine analogues, suppresses the synthesis of DNA. It exhibits cyclospecificity by acting on cells in the S and G1 / S phases. Metabolized in the cell by the action of nucleoside kinases to active diphosphate and triphosphate nucleosides. Diphosphate nucleosides inhibit the action of ribonucleotide reductase (the only enzyme catalyzing the formation of deoxynucleoside triphosphates required for DNA synthesis). Triphosphate nucleosides can be inserted 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 the preparation of the first line: monotherapy causes clinical improvement in 25-40% of patients, and in 10-15% of patients - partial remission of 11-12 weeks duration: 23% of patients live more than a year. When gemcitabine is combined with cisplatin, the effectiveness of treatment is increased to 69%. Gemcitabine is also a strong radiosensitizer even at concentrations lower than cytotoxic.
PHARMACOKINETICS
Distribution
C max gemcitabine (from 3.2 Ојg / ml to 45.5 Ојg / ml) is reached 5 minutes after the end of the infusion. Pharmacokinetic analysis of studies with single and multiple doses shows that V d depends largely on sex. The binding of gemcitabine to plasma proteins is negligible.
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 an inactive metabolite of 2'-deoxy-2 ', 2'-difluoruridine. Less than 10% of the administered intravenous dose is found in the urine in the form of unchanged gemcitabine. Systemic clearance, which ranges from about 30 l / h / m 2 to 90 l / h / m 2 , depends on age and sex. T 1/2 ranges from 42 minutes to 94 minutes. When the recommended dosage regimen is followed, the complete excretion 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
With the combined administration of gemcitabine and paclitaxel, the pharmacokinetics of the drugs do not change.
With the joint administration of gemcitabine and carboplatin, the pharmacokinetics of gemcitabine does not change.
Renal failure of mild to moderate degree (CK 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 (ECOG-BOS scale);
- inoperable, locally-recurrent or metastatic breast cancer after neoadjuvant and / or adjuvant therapy with anthracyclines included in the absence of contraindications to their use as part of combination therapy with paclitaxel;
- Locally distributed or metastatic urothelial cancer (cancer of the bladder, renal pelvis, ureters, urethra);
- Locally distributed or metastatic ovarian cancer as monotherapy or in combination with carboplatin in patients with progression of the disease after the first line of therapy based on platinum-containing drugs;
- locally advanced or metastatic pancreatic cancer;
- locally advanced or metastatic cervical cancer.
DOSING MODE
Gemtaz is injected intravenously into the drip for 30 minutes.
Locally distributed 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 (ECOG-BOS scale)
For monotherapy, the recommended dose of the drug is 1000 mg / m 2 in the 1 st, 8 th and 15 th days of each 28-day cycle.
In combination therapy with cisplatin, the recommended dose of the drug is 1250 mg / m 2 on the 1 st and 8 th day of each 21-day cycle or 1000 mg / m on the 1 st, 8 th and 15 th days of each 28-day cycle Cisplatin is administered at a dose of 70 mg / m 2 on the 1st day of the cycle against a backdrop of the water load after the infusion of gemcitabine.
With combined therapy with carboplatin, the recommended dose is 1000 mg / m 2 or 1200 mg / m 2 on the 1 st and 8 th day of each 21-day cycle. Carboplatin is administered at a dose of 5 mg / ml-min on the 1st day of the cycle after the infusion of gemcitabine.
Inoperable, local-recurring or metastatic breast cancer after neoadjuvant and / or adjuvant therapy with the inclusion of anthracyclines in the absence of contraindications to their use as part of combination therapy with paclitaxel
As the first line therapy for the progression of the disease after neoadjuvant therapy involving anthracyclines, the recommended dose of the drug is 1,250 mg / m 2 on days 1 and 8 in combination with paclitaxel at a dose of 175 mg / m 2 , which is administered after administration of gemcitabine on the 1st day of each 21-day I / O cycle drip for about 3 hours.
Locally prevalent or metastatic urothelial cancer (cancer of the bladder, renal pelvis, ureters, urethra)
With monotherapy, the recommended dose of the drug is 1250 mg / m 2 in the 1 st, 8 th and 15 th days of each 28-day cycle.
In combination therapy, the recommended dose of the drug is 1000 mg / m 2 on days 1, 8 and 15, in combination with cisplatin, which is administered at a dose of 70 mg / m 2 immediately after the infusion of gemcitabine in the 1 st or 2 the day of each 28-day cycle.
Locally distributed or metastatic ovarian cancer as monotherapy or in combination with carboplatin in patients with progression of the disease after the first line of therapy based on platinum-containing drugs
With monotherapy, the recommended dose of the drug is 800-1250 mg / m 2 in the 1 st, 8 th and 15 th days of each 28-day cycle.
In combination therapy, the recommended dose of the drug is 1000 mg / m 2 on days 1 and 8, in combination with carboplatin at a dose of 4 mg / ml-min, which is injected immediately after the infusion of gemcitabine on the 1 st day of each 21-day cycle .
Locally-distributed or metastatic pancreatic cancer
With monotherapy, the recommended dose of the drug is 1000 mg / m 2 once a week for 7 weeks, followed by a weekly break. Then the drug is administered on the 1st, 8th and 15th days of each 28-day cycle.
Localized or metastatic cervical cancer
As part of combination therapy with locally advanced cancer (neoadjuvant) and metastatic cancer, gemcitabine is administered at a dose of 1250 mg / m 2 on the 1 st and 8 th days of each 21-day cycle. Cisplatin is administered at a dose of 70 mg / m 2 after administration of gemcitabine on the first day of the cycle against hyperhydration.
In locally advanced cancers with simultaneous radiotherapy, gemcitabine is administered once a week for 6 weeks at a dose of 125 mg / m 2 , followed by (immediately after administration of gemcitabine) by cisplatin 40 mg / m 2 1-2 h before the onset radiotherapy. Radiation therapy is performed for 28 fractions, in a single focal dose of 1.8 g, 5 days a week to a total focal dose of 50.4 g.
Correction of the dose of the drug in connection with the phenomena of hematological toxicity
Start of treatment cycle
Regardless of the indications, before each injection of the drug it is necessary to evaluate the pure platelets and granulocytes.
The condition for the initiation of treatment is an absolute number of neutrophils of not less than 1500 / ОјL and a platelet count of at least 100,000 / ОјL.
If hematological toxicity develops during the treatment cycle, the dose of gemcitabine may be reduced, or its administration postponed in accordance with the following recommendations:
Modification of the dose of gemcitabine used in monotherapy or in combination with cisplatin in the treatment of bladder cancer, non-small cell lung cancer and pancreatic cancer
Absolute number of neutrophils (in 1 Ојl) Number of platelets (in 1 Ојl) % of the standard dose
> 1000 and> 100 000 100
500-1000 or 50 000-100 000 75
<500 or <50 000 Postpone the introduction *
* With an increase in the number of neutrophils to 500 / ОјL and platelets to 50,000 / ОјL, the administration of gemcitabine can be continued as part of the cycle
Modification of the dose of gemcitabine, used in combination with paclitaxel in the treatment of breast cancer
Absolute number of neutrophils (in 1 Ојl) Number of platelets (in 1 Ојl) % of the standard dose
? 1200 and> 75 000 100
1000- <1200 or 50 000-75 000 75
700- <1000 and? 50 000 50
<700 or <50 000 Postpone the introduction *
* Treatment within the cycle is not resumed. The next administration of gemcitabine is carried out on the 1st day of the next cycle when the amount of neutrophils is restored to at least 1500 / Ојl and platelets to 100,000 / ОјL
Modification of the dose of gemcitabine, used in combination with carboplatin in the treatment of ovarian cancer
Absolute number of neutrophils (in 1 Ојl) Number of platelets (in 1 Ојl) % of the standard dose
> 1500 and> 100 000 100
1000- <1500 or 75 000-100 000 50
<1000 or <75 000 Cancellation of the introduction *
* Treatment within the cycle is not resumed. The next administration of gemcitabine is performed on the 1st day of the next cycle when the amount of neutrophils is reached to at least 1500 / Ојl and platelets to 100,000 / ОјL
The dose of gemcitabine in the next cycle should be reduced by 25% for all indications in cases when the previous cycle showed:
- decrease in the absolute number of neutrophils <500 / ОјL, lasting more than 5 days;
- a decrease in the absolute number of neutrophils <100 / ОјL, lasting more than 3 days;
- febrile neutropenia;
- decrease in the number of platelets <25 000 / ОјL;
- The cycle was delayed more than 1 week due to hematologic toxicity.
Correction of the dose of the drug in connection with the phenomena of nonhematological toxicity
To detect nonhematological toxicity, periodic physical examination and monitoring of liver and kidney functions should be performed. The dose of the drug can be reduced in each subsequent cycle or during the already started cycle, depending on the degree of manifestation of toxicity of the drugs prescribed to the patient. In the case of severe (grade 3 or 4) non-hematologic toxicity, with the exception of nausea / vomiting, gemcitabine therapy should be suspended or reduced in proportion to the decision of the attending physician. The decision to resume treatment is taken by a doctor.
Method of administration
Infusion gemcitabine is usually well tolerated by patients and can be performed on an outpatient basis. In the case of extravasation, the infusion is discontinued and the drug is resumed into another vein. After the introduction of gemcitabine, the patient should be observed for some time.
Patients with impaired hepatic and renal function
Use gemcitabine in patients with hepatic impairment or with impaired renal function should be used with caution. There is no sufficient data on the use of the drug in this category of patients. Renal failure of moderate or moderate severity (glomerular filtration rate from 30 ml / min to 80 ml / min) has no significant effect on the pharmacokinetics of gemcitabine.
Elderly patients (> 65 years)
Gemcitabine is well tolerated by patients older than 65 years. Specific recommendations for changing the dose of the drug for this population are absent.
Children (<18 years old)
Gemcitabine is not recommended for children under the age of 18 due to insufficient information on the safety and efficacy of the drug in this population.
Recommendations for the preparation of a solution for infusion
As a solvent, only 0.9% sodium chloride solution without preservatives is used.
To prepare a solution of the drug in the bottle, slowly inject the necessary amount of 0.9% solution of sodium chloride for injections (not less than the amount indicated in the table below) and gently shake the bottle until the content is completely dissolved.
The dose of the drug in the vial The required volume of 0.9% solution of sodium chloride for injection The volume of reconstituted solution The concentration of gemcitabine in solution
200 mg 5 ml 5.26 ml 40 mg / ml
1000 mg 25 ml 26.3 ml 40 mg / ml
The resulting solution should be clear.
The maximum concentration of the reconstituted solution of gemcitabine should not exceed 40 mg / ml, since at higher concentrations, an incomplete dissolution of the preparation is possible.
A prepared gemcitabine solution containing the desired dose of the preparation is diluted with 0.9% sodium chloride solution for injection in an amount sufficient for a 30-minute IV infusion before administration.
Before parenteral administration of the drug solution, one should be convinced of the absence of undissolved particles in it and the color change of the solution.
The prepared preparation solution is stable from a physical and chemical point of view for 24 hours provided that it was stored at controlled room temperature (20 В° C to 25 В° C). From the 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 not more than 24 hours at room temperature (20 В° C to 25 В° C).
The prepared drug solution is intended for single use only. All unused product must be disposed of.
SIDE EFFECT
Adverse reactions occurring more often than in single 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 hematopoiesis: very often - leukopenia, neutropenia, thrombocytopenia, anemia; often - febrile neutropenia; very rarely - thrombocytosis.
On the part of the digestive system: very often - nausea, vomiting, increased activity of hepatic transaminases (ALT, AST), APF; often - anorexia, diarrhea, constipation, stomatitis, increased bilirubin concentration: rarely - increase in GGT activity.
From the side of the urinary system: very often - hematuria and mild urinary proteinuria; rarely - renal failure, clinical signs and symptoms similar to uremic syndrome (decreased hemoglobin, increased creatinine, urea concentration, and / or lactate dehydrogenase activity in blood serum).
From the skin and subcutaneous tissues: very often - skin rashes, accompanied by itching, alopecia; often - skin itching, increased sweating; rarely - skin ulceration, the formation of blisters; very rarely - severe skin reactions, including desquamation and bullous eruptions.
From the respiratory system: very often - shortness of breath; often - cough, rhinitis; infrequently - bronchospasm, interstitial pneumonitis, pulmonary edema; rarely acute respiratory distress syndrome.
From the cardiovascular system: rarely - lowering blood pressure, myocardial infarction, heart failure, arrhythmia.
From the nervous system: often - headache, increased drowsiness, insomnia.
Other: very often - influenza-like syndrome, peripheral edema; often - fever, chills, asthenia, back pain, myalgia; infrequent - swelling of the face; very rarely - anaphylactic reactions.
CONTRAINDICATIONS
- Pregnancy;
- the period of breastfeeding;
- Children under 18 years of age (lack of sufficient data on effectiveness and safety);
- Hypersensitivity to gemcitabine or other component of the drug.
With caution should prescribe the drug in violation of liver and / or kidney function, oppression of bone marrow hematopoiesis (including on the background of concomitant radiation or chemotherapy), cardiovascular diseases, with metastatic liver damage, hepatitis, alcoholism, while concurrent radiation therapy , acute infectious diseases of a viral, fungal or bacterial nature (including chicken pox, shingles).
PREGNANCY AND LACTATION
Contraindicated in pregnancy, during lactation.
APPLICATION FOR FUNCTIONS OF THE LIVER
Gemcitabine should be used with caution in patients with impaired renal function. There is no sufficient data on the use of the drug in this category of patients. Renal failure of moderate or moderate severity (glomerular filtration rate from 30 ml / min to 80 ml / min) has no significant effect on the pharmacokinetics of gemcitabine
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Gemcitabine should be used with caution in patients with hepatic insufficiency. There is no sufficient data on the use of the drug in this category of patients.
APPLICATION FOR CHILDREN
Gemcitabine is not recommended for children under the age of 18 due to insufficient information on the safety and efficacy of the drug in this population.
APPLICATION IN ELDERLY PATIENTS
Gemcitabine is well tolerated by patients older than 65 years. Specific recommendations for changing the dose for this population are not available.
SPECIAL INSTRUCTIONS
Treatment with Gemtaz can be carried out only under the supervision of a physician with experience in cancer chemotherapy.
Prior treatment with cytostatics increases the incidence and severity of leukopenia and thrombocytopenia (progressive decrease in leukocyte and platelet counts may occur after completion of therapy). It is necessary to carry out regular monitoring of peripheral blood picture, liver enzymes and creatinine in the blood serum. Increasing the infusion duration and frequency of administration leads to high toxicity.
Bone marrow suppression is necessary to suspend treatment or adjust the dose. Women of childbearing age and men need to use effective contraceptive measures.
The prepared solution should be kept at room temperature (15 В° to 30 В° C) and used within 24 hours. It should not freeze because Crystallization may occur. Optimal mode for safe administration of gemcitabine in combination therapeutic regimens with radiotherapy have not yet been defined.
Impact on the ability to drive vehicles and manage mechanisms
During the period of treatment must be careful when driving and occupation of other potentially hazardous activities that require high concentration and psychomotor speed reactions.
OVERDOSE
Symptoms: mielodeprescia, anemia (excessive tiredness or weakness), leukopenia, neutropenia, manifestation of infection (fever, cough, hoarseness, pain in the side or back pain, painful or difficult urination), thrombocytopenia (bleeding, bleeding, black tarry stool, blood in the urine and feces, ecchymosis), paresthesia, pronounced skin rash.
Treatment: in case of suspected overdose patient must be under constant medical supervision, including the blood count of formula, if necessary - symptomatic treatment. The antidote is unknown.
DRUG INTERACTION
Radiation therapy
Concomitant radiation therapy (simultaneously with administration of the drug gemcitabine or intervals <7 days before starting 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 2for 6 consecutive weeks in conjunction with radiation therapy to the chest area, was marked by significant toxicity in the form of severe and potentially life-threatening inflammation of the mucous membranes, especially esophagitis and pneumonitis, especially in patients with large amounts 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 phase II studies in patients with non-small cell lung cancer radiotherapy was performed at a dose of 60 g conjunction with administering gemcitabine (600 mg / m 2 4 times) and cisplatin (80 mg / m 22-fold) for 6 weeks. Sequential therapy (break> 7 days): substantial 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 drugs that cause depression of bone marrow function, and potentiate the effect of radiation therapy and additive depress bone marrow function. Azathioprine, chlorambucil, corticosteroids, cyclophosphamide, cyclosporine, mercaptopurine, and other immunosuppressive agents increase the risk of infection. When administered live viral vaccines is possible intensification vaccine virus replication and increased side effects when administered inactivated vaccines - suppression of antiviral antibodies.
Compatibility
Compatibility studies have not been conducted Gemtaz drug.
Mix preparation Gemtaz with other drugs is not recommended.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be stored in a place protected from light, inaccessible to children, at a temperature of no higher than 25 В° C. Shelf life - 3 years.
