Composition, form of production and packaging
Lyophilizate for the preparation of a solution for infusions in the form of a powder or a mass of white or almost white.
1 f.
gemcitabine hydrochloride 227.72 mg,
which corresponds to the content of gemcitabine 200 mg
Excipients: mannitol - 200 mg, sodium acetate trihydrate - 12.5 mg, hydrochloric acid - qs for pH adjustment, sodium hydroxide - qs for pH adjustment.
Glass bottles (1) - cardboard packs.
Lyophilizate for the preparation of a solution for infusions in the form of a powder or a mass of white or almost white.
1 f.
gemcitabine hydrochloride 1138.6 mg,
which corresponds to the content of gemcitabine 1000 mg
Excipients: mannitol - 1000 mg, sodium acetate trihydrate - 62.5 mg, hydrochloric acid - qs for pH adjustment, sodium hydroxide - qs for pH adjustment.
Glass bottles (1) - cardboard packs.
Lyophilizate for the preparation of a solution for infusions in the form of a powder or a mass of white or almost white.
1 f.
gemcitabine hydrochloride 1594.04 mg,
which corresponds to the content of gemcitabine 1400 mg
Excipients: mannitol - 1400 mg, sodium acetate trihydrate - 87.5 mg, hydrochloric acid - qs for pH adjustment, sodium hydroxide - qs for pH adjustment.
Glass bottles (1) - cardboard packs.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2015.
PHARMACHOLOGIC EFFECT
Antitumor drug, antimetabolite group of pyrimidine analogues, suppresses the synthesis of DNA. It exhibits cyclospecificity by acting on cells in phase S and at the interface of G1 and S phases. 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 (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 lysis (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, of which gemcitabine di- and triphosphates are considered active.
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.
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 and in monotherapy in elderly patients with functional status equal to 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 advanced 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
The drug is injected into / in the drip for 30 minutes.
Non-small cell lung cancer
With 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 2 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 the Heimite preparation.
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 5.0 mg / ml / min AUC on the 1st day of the cycle after infusion of the Heimite preparation.
Mammary cancer
In combination therapy as 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, which is administered after the administration of the Heime preparation in dose of 175 mg / m 2 on the 1st day of each 21-day I / O cycle for approximately 3 hours.
Urothelial cancer
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 the drug Gemita in the 1 st or The 2nd day of each 28-day cycle.
Ovarian Cancer
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.
Pancreas 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.
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 1 st and 8 th days of each 21-day cycle. Cisplatin is administered after the administration of the drug Gemita in a dose of 70 mg / m 2 on the 1st day of the cycle against a background of hyperhydration.
In locally advanced cancers with simultaneous radiation therapy, Gemita is given once a week for 6 weeks at a dose of 125 mg / m 2 , followed by (immediately after the administration of the drug Gemita) by cisplatin 40 mg / m 2 for 1-2 hours before the beginning of radiation therapy. 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.
Change in the dose of the drug due to the phenomenon of hematological toxicity
Start of treatment cycle
Regardless of the indications, before each administration of the drug it is necessary to evaluate the number of 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 the drug Gemita may be reduced, or its administration postponed in accordance with the following recommendations.
Modification of the dose of the drug Gemita, 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 previous 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 introduction of the Heimite drug can be continued within the cycle.
Modification of the dose of the drug Gemita, 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 injection of the drug Gemita 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.
Modification of the dose of the drug Gemita, 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 Postpone the introduction *
* Treatment within the cycle is not resumed. The next injection of the drug Gemita is carried out 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 the drug Gemita on the next cycle should be reduced by 25% for all indications in cases when the previous cycle observed:
- 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.
Method of administration
Infusion injection of the drug Gemita is usually well tolerated by patients and can be performed on an outpatient basis. In the case of extravasation, the infusion is stopped and the drug is resumed into another vein. After the introduction of the drug, the patient must be observed for some time.
Use the drug Gemita in patients with hepatic insufficiency or with impaired renal function should be carried out 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.
The drug is well tolerated by elderly patients older than 65 years . Specific recommendations for changing the dose of the drug for this population are absent.
It is not recommended to administer Gemita to children under the age of 18 due to insufficient information on the safety and efficacy of the drug in this population.
Rules 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 for infusions, the contents of the 200 mg bottle are dissolved in at least 5 ml, 1000 mg in at least 25 ml, and 1400 mg in at least 35 ml of a 0.9% solution of sodium chloride for injection. Each vial is gently shaken until the lyophilizate is completely dissolved. The resulting solution should be clear.
The maximum concentration of gemcitabine should not exceed 40 mg / ml. Solutions prepared with a concentration higher than 40 mg / ml may be accompanied by incomplete dissolution.
A prepared solution of the preparation of Gemita 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, it is necessary to visually monitor the prepared solution for mechanical impurities and discoloration.
The prepared solution of the Heime preparation is stable from a physical and chemical point of view for 24 hours provided that it was stored at a 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° to 25 В° C).
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%).
On the part of the organs of 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 (AST, ALT), 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; Rare renal failure, clinical signs and symptoms similar to hemolytic uremic syndrome (decreased hemoglobin, thrombocytopenia, increased bilirubin, creatinine, urea, and / or LDH serum activity).
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; infrequently - 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 the active substance or to any of the excipients.
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 use of the drug during pregnancy and lactation (breastfeeding).
APPLICATION FOR FUNCTIONS OF THE LIVER
With caution: if kidney function is impaired. During treatment, a regular assessment of renal function should be performed.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
With caution: with a violation of liver function, with metastatic liver damage, hepatitis. During treatment, a regular evaluation of liver function should be performed.The introduction of the drug Gemita with metastases in the liver, with hepatitis and alcoholism in the anamnesis, 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 the drug Gemita can be carried out only under the supervision of a doctor who has experience in carrying out antitumoral chemotherapy.
Before each injection of the drug, it is necessary to determine the leukocyte formula and the number of platelets 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.
It is necessary to conduct regular examination of the patient and assess the function of the kidneys and liver.
The introduction of the drug Gemita with metastases in the liver, with hepatitis and alcoholism in the anamnesis, as well as with cirrhosis increases the risk of hepatic insufficiency.
If there are signs of development of adverse events on the part of the respiratory system (for example, pulmonary edema, interstitial pneumonitis, or respiratory distress syndrome in adults), treatment should be discontinued and appropriate therapy prescribed.
When the first signs of microangiopathic hemolytic anemia, such as a rapid decrease in hemoglobin with concomitant thrombocytopenia, an increase in serum bilirubin, creatinine, nitrogen, urea concentration or an increase in LDH activity, the drug should be withdrawn. Increasing the duration of infusion and the frequency of administration leads to an increase in toxicity.
Depending on the degree of toxicity, the dose can be reduced during each cycle or with the onset of a new cycle stepwise.
During treatment and for 6 months after the termination of therapy with the preparation of Gemita, reliable methods of contraception should be used. 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.
Impact on the ability to drive vehicles and manage mechanisms
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 high concentration and psychomotor speed reactions, which requires compliance with caution.
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 of treatment toxicity levels remained acceptable. In case of suspected overdose gemcitabine should be monitored and set the degree of cytopenia maintenance therapy if necessary.
DRUG INTERACTION
Radiation therapy
Concomitant radiation therapy (simultaneously with administration of the drug Gemita 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 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 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.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be stored out of reach of children at a temperature of no higher than 25 В° C. Do not freeze. Shelf life - 2 years.
