Composition, form of production and packaging
Lyophilizate for the preparation of a solution for infusions of white or almost white color.
1 f.
gemcitabine hydrochloride 1138.5 mg,
which corresponds to the content of gemcitabine 1000 mg
Excipients: mannitol, sodium acetate trihydrate, sodium hydroxide, hydrochloric acid.
Vials (1) - packs of cardboard.
Lyophilizate for the preparation of a solution for infusions of white or almost white color.
1 f.
gemcitabine hydrochloride 1707.8 mg,
which corresponds to the content of gemcitabine 1500 mg
Excipients: mannitol, sodium acetate trihydrate, sodium hydroxide, hydrochloric acid.
Vials (1) - packs of cardboard.
Lyophilizate for the preparation of a solution for infusions of white or almost white color.
1 f.
gemcitabine hydrochloride 227.7 mg,
which corresponds to the content of gemcitabine 200 mg
Excipients: mannitol, sodium acetate trihydrate, sodium hydroxide, hydrochloric acid.
Vials (1) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2011.
PHARMACHOLOGIC EFFECT
Antitumor agent, antimetabolite of the group of pyrimidine analogs, suppresses the synthesis of DNA. It exhibits cyclospecificity by acting on cells in the S and Gl / 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). Trisphosphate 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 death (apoptosis).
Gemcitabine is also a strong radiosensitizer even at concentrations lower than cytotoxic.
PHARMACOKINETICS
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.
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 (dFdCMP, dFdCDP and dFdCTP), of which dFdCDP and dFdCTP are considered active.
Gemcitabine is quickly excreted from the body with urine mainly as an inactive metabolite of 2'-deoxy-2 ', 2'-difluoruridine. Less than 10% of the administered IV 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: the rate of excretion in women is about 25% lower than that of men; Both in men and in women, the rate of excretion decreases with age.
T 1/2 ranges from 42 minutes to 94 minutes. If the recommended dosing regimen is followed, the complete excretion of gemcitabine occurs within 5-11 h from the onset of nf fusion. When administered once a week, gemcitabine does not accumulate in the body.
Combination therapy with gemcitabine and paclitaxel. With the combined administration of gemcitabine and paclitaxel, the pharmacokinetics of the drugs do not change.
Combination therapy with gemcitabine and carboplatin. With the joint administration of gemcitabine and carboplatin, the pharmacokinetics of gemcitabine does not change.
Impaired renal function. Renal failure of mild to moderate degree (creatinine clearance 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 functional status equal to 2;
- Unresectable, local-recurring or metastatic breast cancer as part of combination therapy with paclitaxel after neoadjuvant and / or adjuvant therapy with anthracyclines included in the absence of contraindications to their prescription;
- Locally distributed or metastatic urothelial cancer (cancer of the bladder, renal pelvis, ureters, urethra);
- Locally disseminated or metastatic epithelial 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 spread or metastatic pancreatic cancer;
- Locally advanced or metastatic cervical cancer.
DOSING MODE
Gemcitabine is injected intravenously into the drip for 30 minutes.
Non-small cell lung cancer
Monotherapy: the recommended dose of the drug is 1000 mg / m 2 at 1, 8 and 15 days of each 28-day cycle.
Combination therapy with cisplatin: the recommended dose of the drug is 1250 mg / m 2 on the 1 and 8 day of each 21-day cycle or 1000 mg / m 2 at 1, 8 and 15 days of each 28-day cycle. Cisplatin is administered at a dose of 70-100 mg / m 2 in the 1st day of the cycle against the background of the water load after the infusion of gemcitabine.
Combination therapy with carboplatin : the recommended dose of the drug is 1000 mg / m 2 or 1200 mg / m 2 at 1 and 8 days of each 21-day cycle. Carboplatin is administered at a dose of AUC 5.0 mg / ml * min on the 1st day of the cycle after the infusion of gemcitabine.
Mammary cancer
Combination therapy: as first-line therapy for progression of post-neoadjuvant therapy, including anthracyclines; the recommended dose of the drug is 1250 mg / m 2on days 1 and 8 in combination with paclitaxel at a dose of 175 mg / m 2 , which is administered on the 1st day of each 21-day I / O cycle drip for about 3 h, before the introduction of gemcitabine.
Urothelial cancer
Monotherapy: the recommended dose of the drug is 1250 mg / m 2 at 1, 8 and 15 days of each 28-day cycle.
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.
Epithelial ovarian cancer
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.
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 AUC4.0 mg / ml * min, which is injected immediately after the infusion of gemcitabine on the 1st day of each 21- day cycle.
Pancreas cancer
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.
Cervical cancer (locally advanced or metastatic)
Combination therapy: With locally advanced cancer (neoadjuvant) and metastatic cancer, gemcitabine is administered at a dose of 1250 mg / m 2 on the first and 8th days of each 21-day cycle. Cisplatin is administered at a dose of 70 mg / m 2 after the administration of gemcitabine on the first day of the cycle against hyperhydration.
Corrector 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 enter it 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> 100000 100
500 - 1000 or 50000 - 100000 75
<500 or <50000 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> 75000 100
1000 - <1200 or 50000 - 75000 75
700 - <1000 and? 50000 50
<700 or <50000 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 caste) Number of platelets (in 1 Ојl) % of standard dose
> 1500 and? 100000 100
1000 - 1500 or 75000 - 100000 50
<1000 or <75000 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 absolute pure 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;
- reduction of pure platelets <25000 / 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 dosage, depending on 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.
Special patient groups
Patients with impaired hepatic and renal function: use gemcitabine in patients with hepatic insufficiency or with impaired renal function should be taken with caution, since there is insufficient 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 of age): 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 of age: 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 infusions
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 dosage 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 38 mg / ml
1000 mg 25 ml 26.3 ml 38 mg / ml
1500 mg 37.5 ml 39.5 ml 38 mg / ml
The resulting solution should be clear.
The maximum concentration of the reconstituted solution of gemcitabine should not exceed 38 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 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: 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 (aspartate aminotransferase, alanine aminotransferase), alkaline phosphatase; often - anorexia, diarrhea, constipation, stomatitis, increased bilirubin concentration; rarely - increased activity of gamma-glutamyltransferase; frequency can not be estimated on the basis of available data - ischemic colitis, toxic liver damage, including hepatic insufficiency with a lethal outcome.
From the side of the urinary system: very often - hematuria and mild urinary proteinuria; frequency can not be estimated on the basis of available dacha - acute renal failure, clinical signs and symptoms similar to hemolytic-uremic syndrome (decrease in hemoglobin, thrombocytopenia, increase in bilirubin, creatinine, urea and / or lactate dehydrogenase in blood serum).
From the skin and skin appendages: very often - skin rashes, accompanied by itching, alopecia; often - skin itching, increased sweating; rarely - ulceration, blistering, very rarely - severe skin reactions, including desquamation and bullous eruptions; the frequency can not be assessed - Lyell's syndrome, Stevens-Johnson syndrome.
From the respiratory system: very often - shortness of breath; often - cough, rhinitis, infrequently, bronchospasm, vestitivial pneumonia; the frequency can not be assessed - pulmonary edema, acute respiratory distress syndrome.
From the cardiovascular system: rarely - lowering blood pressure, myocardial infarction, the frequency can not be assessed - arrhythmia (mostly supraventricular), heart failure, clinical signs of peripheral vasculitis and gangrene.
From the nervous system: often - headache, increased drowsiness, insomnia; the frequency can not be assessed - a stroke.
Other: very often - a feeling of malaise, flu-like syndrome, peripheral edema; often - fever, chills, asthenia, back pain, myalgia; rarely - swelling of the face, reactions at the injection site; very rarely - anaphylactic reactions.
CONTRAINDICATIONS
- hypersensitivity to the active substance or to any of the excipients;
- pregnancy and the period of breastfeeding;
- Children under 18 years of age (lack of sufficient data on effectiveness and safety).
With caution: if the liver and / or kidney function is impaired, bone marrow hematopoiesis is suppressed (including on the background of concomitant radiation or chemotherapy), cardiovascular diseases in anamnesis, with metastatic liver damage, hepatitis, alcoholism, concomitant radiotherapy, acute infectious diseases of a viral, fungal or bacterial nature (including chicken pox, shingles).
PREGNANCY AND LACTATION
Contraindicated: pregnancy and lactation.
APPLICATION FOR FUNCTIONS OF THE LIVER
With caution in the violation of kidney function. During treatment it is necessary to conduct regular examination of the patient and evaluation of kidney function.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
With caution in the violation of liver function, with metastatic liver damage, hepatitis. During treatment it is necessary to conduct regular examination of the patient and assess the liver function. The introduction of gemcitabine in metastases in the liver, with hepatitis and alcoholism in history, as well as with cirrhosis increases the risk of hepatic insufficiency.
APPLICATION FOR CHILDREN
Contraindicated in children under 18 years of age (lack of sufficient data on efficacy and safety).
APPLICATION IN ELDERLY PATIENTS
The drug is well tolerated by patients older than 65 years. Specific recommendations for changing the dose of the drug for this population are absent.
SPECIAL INSTRUCTIONS
Treatment with gemcitabine can be done only under the supervision of a doctor who has experience in the use of antitumor chemotherapy.
Before each administration of gemcitabine, it is necessary to control the number of platelets, leukocytes and granulocytes in the blood. At signs of oppression of bone marrow function caused by the drug, it is necessary to suspend treatment or adjust the dose.
Usually, the suppression of bone marrow function is of a short-term nature, does not require a dose reduction, and rarely leads to the need for interruption of treatment. Peripheral blood counts may continue to worsen after interruption of gemcitabine therapy.
When using gemcitabine in combination with other antitumor drugs, the risk of cumulative suppression of bone marrow function should be considered.
It is necessary to conduct regular examination of the patient and assess the function of the kidneys and liver.
Gemcitabine with 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, interstitial pneumonitis and respiratory distress syndrome in adults) patients discontinue gemcitabine treatment 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, urea nitrogen, or increasing lactate dehydrogenase activity, gemcitabine should be canceled.
Increasing the infusion duration and frequency of administration leads to an increase in toxicity.
The risk of skin reactions is increased in the presence of radiation therapy history.
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 therapy with gemcitabine should use reliable methods of contraception. Men receiving gemcitabine recommended resort to semen cryopreservation prior to treatment because of the risk of sterility caused by the use of this drug
in the treatment of patients who are on controlled diet to consider sodium content of the sodium formulation in the following amounts:
Gemcitabine 200 mg vial contains Medac 3.5 mg (<1 mmol) sodium
vial 1000 mg Gemcitabine Medac contains 17.5 mg (<1 mmol) sodium
vial 1500 mg Gemcitabine Medac contains 26.3 mg (<1 mmol) of sodium.
Effect on ability to drive and use machines.Data on the effect of gemcitabine therapy on the ability to drive and use machines are not available, however, some side effects of the drug such as hypersomnia, may adversely affect the ability to perform such activities. During treatment with gemcitabine should be careful when driving and other lesson potentially dangerous activities which require high concentration and psychomotor speed reactions.
OVERDOSE
Symptoms: mielodeprescia, paresthesia, severe skin rash. When gemcitabine administered at doses up to 5700 mg / m 2 / drip for 30 minutes every 2 weeks for signs of overdose was not observed. The antidote to gemcitabine is unknown.
In case of suspected overdose gemcitabine should be monitored and set the degree of cytopenia symptomatic therapy if necessary.
DRUG INTERACTION
Specific interaction studies of gemcitabine have been conducted.
Radiation therapy
Concomitant radiation therapy (simultaneously with administration of gemcitabine or <7 days interval before 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 radiosensibilziruyuschey activity. In one study where patients with NSCLC was prepared gemcitabine 1000 mg / m 2for 6 consecutive weeks in combination with therapeutic radiation to the chest area was marked significant toxicity in the form of heavy and potentially life-threatening mucositis mainly esophagitis and pneumonitis, especially in patients with a large volume of tissue irradiation (median volume of irradiated tissue 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 predictable toxicity profile. Thus, in one of phase II studies in patients with non-small cell lung cancer radiation therapy at a dose of 60 Gy in 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): from existing data, gemcitabine more than 7 days prior to the radiotherapy, or more than 7 days after se 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 (eg., Esophagitis, colitis and pneumonia).
Immunosuppressants (azathioprine, chlorambucil, corticosteroids, cyclophosphamide, cyclosporine, mercaptopurine) increase the risk of infections.
Other types of interaction
While the use of live virus vaccines is possible intensification vaccine virus replication process gain its side / adverse effects and / or reduce the production of antibodies in the patient's body in response to the vaccine. Therefore, due to the risk of systemic, possibly fatal complications, particularly in patients with decreased immune status, the interval between the application of such vaccines and gemcitabine should be at least 3 months or more (up to 12 months), depending on the immune status of the patient.
Gemcitabine compatibility studies have not been conducted. Gemcitabine can not mix with other drugs.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
In the dark place at a temperature of no higher than 25 В° C. Keep out of the reach of children!
Shelf life. 2.5 years Do not use after the expiry date stated on the package.
