Composition, form of production and packaging
Lyophilizate for the preparation of a solution for infusions in the form of a porous mass from white to almost white.
1 f.
gemcitabine hydrochloride 1.14 g,
which corresponds to the content of gemcitabine 1 g
Excipients: mannitol - 1 g, sodium acetate trihydrate - 103.7 mg (corresponding to sodium acetate, anhydrous - 62.5 mg), sodium hydroxide (1M solution) to pH 3.0 (2.8-3.2).
Bottles of colorless glass with a capacity of 50 ml (1) - packs of cardboard.
Lyophilizate for the preparation of a solution for infusions in the form of a porous mass from white to almost white.
1 f.
gemcitabine hydrochloride 228 mg,
which corresponds to the content of gemcitabine 200 mg
Auxiliary substances: mannitol - 200 mg, sodium acetate trihydrate - 20.74 mg (corresponding to sodium acetate - anhydrous - 12.5 mg), sodium hydroxide (1M solution) to pH 3.0 (2.8-3.2).
Vials of colorless glass with a capacity of 10 ml (1) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2013.
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 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 that catalyzes the formation, 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).
Gemcitabine is also a strong radiosensitizer even in concentrations lower than cytotoxic.
PHARMACOKINETICS
Pharmacokinetic data were evaluated when infusions were administered to patients within 0.4-1.2 hours of doses from 500 to 2592 mg / m 2 .
C max in blood plasma (measured within 5 min after the end of infusion) is from 3.2 to 45.5 Ојg / ml. After a single 30-minute infusion at a dose of 1 g / m 2 , the blood plasma concentration of the starting substance is above 5 Ојg / ml for about 30 min after the end of the infusion and above 0.4 Ојg / ml for an additional hour thereafter.
Linkage to plasma proteins is low (less than 10%).
V d in the central chamber for women is 12.4 l / m 2 and 17.5 l / m 2 for males (with interindividual variability of 91.9%). V d into the peripheral chamber 47.4 l / m 2 .The volume of the peripheral compartment does not depend on the sex.
Metabolized in cells of the liver, kidneys, blood and other tissues by the enzyme cytidine deaminase. At intracellular metabolism of gemcitabine, mono-, di- and triphosphates are formed, the latter two being active metabolites. These intracellular metabolites are not detected in blood plasma and urine. The primary metabolite of 2'-deoxy-2 ', 2'-difluoruridine is not active, it is found in blood plasma and urine. After a week, 92-98% of gemcitabine is metabolized.
T 1/2 depends on sex and age and is 42-94 minutes. When gemcitabine is administered in the recommended doses, the drug is withdrawn 5 to 11 hours after the start of the infusion.
Systemic clearance varies from 29.2 l / h / m 2 to 92.2 l / h / m 2 and depends on age and sex (with an interindividual variability of 52.2%). In women, the clearance of the drug is slightly lower than that of men (approximately 25%). With age, the clearance values ​​decrease for both men and women. With the introduction of gemcitabine in the form of an infusion of 30 min with a dose of 1 g / m 2 , a reduction in the dose of the drug in both men and women is not required with a decrease in clearance values.
Kidney clearance is 2-7 l / h / m 2 .
It is excreted mostly by the kidneys (99%) and less than 1% by the intestine. Less than 10% of the drug is excreted by the kidneys unchanged.
When administered once a week, gemcitabine is not accumulated in the body.
Pharmacokinetics in special clinical cases
When combined therapy with paclitaxel, pharmacokinetics is not impaired in both components.
With combined therapy with carboplatin, the pharmacokinetics of gemcitabine is not impaired.
Impaired renal function
With renal insufficiency of mild and moderate severity (glomerular filtration level from 30 ml / min to 80 ml / min), there was no significant effect on 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 spread 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-Aktavis is injected intravenously into the drip for 30 minutes.
In non-small cell lung cancer (locally advanced or metastatic) in the form of monotherapy, the recommended dose of the drug is 1000 mg / m 2 at 1, 8 and 15 days of each 28-day cycle.
When used in combination therapy with cisplatin, the recommended dose of the drug is 1250 mg / m 2 on days 1 and 8 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 on the first day of the cycle after gemcitabine infusion on a background of hyperhydration.
When used as a combination therapy with carboplatin, the recommended dose is 1000 mg / m 2 or 1200 mg / m 2 on days 1 and 8 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.
In breast cancer (locally advanced or metastatic) in the form of monotherapy in the progression of the disease after therapy of the first line, including anthracyclines in the absence of contraindications to them, the recommended dose of the drug is 1000-1200 mg / m 2 at 1, 8 and 15 days of each 28-day cycle.
When used as a first-line therapy in combination therapy, after neoadjuvant and / or adjuvant therapy involving anthracyclines, the recommended dose is 1250 mg / m2 on days 1 and 8 in combination with paclitaxel, which is given after gemcitabine in a dose 175 mg / m 2 per day of each 21-day I / O cycle drip for about 3 hours.
In urothelial cancer (locally advanced, metastatic and superficial) in the form of monotherapy, the recommended dose of the drug is 1250 mg / m 2 at 1, 8 and 15 days of each 28-day cycle.
When used in combination therapy, the recommended dose of the drug is 1000 mg / m 2 at 1, 8 and 15 days in combination with cisplatin, which is administered at a dose of 70 mg / m 2 , immediately after the infusion of gemcitabine on or on day 2 of each 28- day cycle.
In epithelial ovarian cancer (locally or metastatically) in the form of monotherapy, the recommended dose of the drug is 800-1250 mg / m 2 , on days 1, 8 and 15 of each 28-day cycle.
When used 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 4.0 mg / ml * AUC, which is injected immediately after the infusion of gemcitabine on day 1 of each 21-day cycle.
In pancreatic cancer (locally advanced or metastatic) in the form of monotherapy, the recommended dose of the drug is 1000 mg / m 2 once a week for 7 weeks, followed by a one-week break. The preparation is then administered on days 1, 8 and 15 of each 28-day cycle.
With cervical cancer (locally advanced or metastatic), combined therapy is provided. In locally advanced cancer with sequential chemotherapy and radiotherapy (neoadjuvant) and metastatic cancer, gemcitabine is administered at a dose of 1250 mg / m 2 on days 1 and 8 of each 21-day cycle. Cisplatin is administered after administration of gemcitabine at a dose of 70 mg / m 2 per day of the cycle against hyperhydration.
In locally advanced cancer with simultaneous chemotherapy and radiation therapy, gemcitabine is administered once a week 1-2 hours prior to the initiation of radiation therapy at a dose of 125 mg / m 2 , followed by (after gemcitabine administration) by cisplatin 40 mg / m 2 .
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 introduction, gemcitabine should be monitored the number of platelets, white blood cells and granulocytes in the blood. At signs of oppression of bone marrow function, it is necessary to suspend treatment or adjust the dose.
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.
In case of development of hematological toxicity, the dose of gemcitabine can be reduced, or the drug administration should be postponed in accordance with the following scheme.
Modification of the dose of gemcitabine used in monotherapy or in combination with cisplatin in the treatment of urothelial 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 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 previous 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 number 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 previous dose
> 1500 and? 100000 100
1000-1500 or 75000-100000 50
<1000 or <75000 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 number of neutrophils is restored 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:
- a 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 <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 case of severe (grade 3 or 4) non-hematologic toxicity, with the exception of cases of nausea / vomiting, gemcitabine therapy should be suspended or reduced depending on the decision of the attending physician. The decision to resume treatment is taken by a doctor.
The data proving that elderly patients need to adjust the dose are not available, although the clearance of gemcitabine and T 1/2 change with age.
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 mild or moderate severity (glomerular filtration rate from 30 ml / min to 80 ml / min) has no significant effect on the pharmacokinetics of gemcitabine.
The use of gemcitabine in children has not been studied.
Rules for the preparation of a solution for infusion
As a solvent, only 0.9% solution of sodium chloride is used (without preservatives).
C max gemcitabine should not exceed 40 mg / mL. In solutions prepared with a concentration of more than 40 mg / ml, an incomplete dissolution of the lyophilizate is possible.
1. For the preparation of the solution, it is necessary to adhere to the requirements for the preparation of solutions for intravenous administration.
2. To prepare a solution for infusion, the contents of the 200 mg bottle are dissolved in 5 ml, and 1 g in 25 ml of a 0.9% solution of sodium chloride for injection (without preservatives). The total volume after dilution is 5.26 ml (for 200 mg) and 26.3 ml (for 1000 mg), respectively. At this dilution, the concentration of gemcitabine is 38 mg / ml, taking into account the volume of lyophilizate. The vial should be shaken until the lyophilizate is completely dissolved. A prepared gemcitabine solution containing the desired dose of the preparation is diluted with 0.9% sodium chloride solution for injections (without preservatives) before administration, in an amount sufficient for a 30-minute IV infusion. The resulting solution should be transparent, from colorless to pale yellow.
3. Before parenteral administration, it is necessary to visually monitor the prepared solution for mechanical impurities and discoloration. Do not inject the solution if particles are found in it.
SIDE EFFECT
Adverse reactions occurring more often than in single cases are listed according to the following gradation: very often (> 10%); often (> 1%, <10%); infrequently (> 0.1%, <1%); rarely (> 0.01%, <0.1%); very rarely (<0.01%).
On the part of the hematopoiesis system: often - leukopenia, thrombocytopenia, anemia; very rarely - thrombocytosis.
From the digestive system: very often - nausea, vomiting, increased activity of "liver" transaminases, alkaline phosphatase; often - anorexia, diarrhea, constipation, stomatitis, increased bilirubin concentration; rarely - increased activity of alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase, alkaline phosphatase; the frequency is unknown - ischemic colitis, serious complications resulting from hepatotoxicity, including hepatic insufficiency, fatal.
From the urinary system: very often - mild proteinuria, hematuria; frequency unknown - renal failure, clinical signs and symptoms similar to hemolytic uremic syndrome (decreased hemoglobin, thrombocytopenia, increased bilirubin, creatinine, urea concentration and / or lactate dehydrogenase activity in blood serum).
From the skin and soft tissues: very often - a skin rash, usually accompanied by itching, alopecia; often - increased sweating, itching; rarely - ulceration, the formation of vesicles and wounds on the skin; very rarely - severe reactions from the skin, including desquamation of the epithelium and biliary rash; frequency unknown - Lyell syndrome, Stevens-Johnson syndrome.
From the respiratory system: very often - shortness of breath; often - cough, rhinitis; infrequently - bronchospasm, interstitial pneumonia, frequency unknown - pulmonary edema, acute respiratory distress syndrome adults.
From the cardiovascular system: rarely - lowering blood pressure, myocardial infarction; frequency unknown - stroke, heart failure, arrhythmia (usually supraventricular), clinical signs of peripheral vasculitis and gangrene.
From the side of the central nervous system: often - headache, drowsiness, insomnia.
Local reactions: rarely - reactions at the injection site, usually light in nature.
Other: very often - the flu-like syndrome (accompanied by the following symptoms: fever, headache, chills, myalgia, asthenia and anorexia, also reported on the development of cough, rhinitis, malaise, increased sweating and sleep disturbance), peripheral swelling, including swelling of the face (like rule puffiness occurs after stopping the drug); often - fever, chills, asthenia, back pain, myalgia; very rarely anaphylactoid reactions; frequency unknown - radiation toxicity.
CONTRAINDICATIONS
hypersensitivity;
- pregnancy, lactation;
- Children under 18 years of age (effectiveness and safety not studied).
With caution: hepatic failure, severe renal failure, oppression of bone marrow hematopoiesis (including on the background of concomitant radiation or chemotherapy), acute infectious diseases of viral, fungal or bacterial nature (including chicken pox, shingles).
PREGNANCY AND LACTATION
There is insufficient data on the use of Gemcitabine-Actavis during pregnancy. The use of the drug during pregnancy is contraindicated. It is not known whether gemcitabine is excreted in breast milk. If Gemcitabine-Aktavis is used, breast-feeding should be discarded.
APPLICATION FOR FUNCTIONS OF THE LIVER
With caution: severe renal failure.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
With caution: liver failure.
The introduction of gemcitabine in hepatitis, with cirrhosis increases the risk of developing liver failure. It is necessary to carry out regular monitoring of the picture of peripheral blood, the activity of "liver" transaminases and the content of creatinine in the blood serum.
APPLICATION FOR CHILDREN
Contraindicated in children and adolescents under 18 years.
SPECIAL INSTRUCTIONS
Treatment with Gemcitabine Aktavis can be done only under the supervision of a doctor who has experience in the use of antitumor chemotherapy.
The drug is well tolerated with an infusion and can be administered on an outpatient basis.
In the event of ekstravazitsii infusion should be stopped and continue the introduction of the drug through another vein. You should carefully monitor the condition of the patient after administration of the drug.
Hematological toxicity
Gemcitabine can inhibit bone marrow function, which can manifest as leukopenia, thrombocytopenia and anemia. When bone marrow function is necessary to suspend treatment or adjust the dose.
Prior treatment with cytostatics increases the incidence and severity of leukopenia and thrombocytopenia (progressive decrease in the number of leukocytes and platelets can be observed after completion of therapy).
Patients with depression of bone marrow blood drug should be used with caution.
Liver failure
Gemcitabine with metastases in the liver, hepatitis, alcoholism and a history of hepatic cirrhosis increases the risk of liver failure. It is necessary to carry out regular monitoring of peripheral blood picture, the activity of "liver" transaminases and creatinine in serum.
Increasing the infusion duration and frequency of administration leads to an increase in toxicity.
Other precautions
Women and men of reproductive age during treatment with gemcitabine and for at least 6 months after therapy should use reliable methods of contraception. In case of pregnancy the patient should immediately notify your doctor. Man before treatment with gemcitabine-Actavis should deliver sperm for cryopreservation, since, after treatment of infertility may develop.
Do not enter live vaccine during treatment with gemcitabine.
In view of the possible development of adverse events in the cardiovascular
system during treatment with gemcitabine should use caution in patients with diseases of the cardiovascular system in history.
In the treatment of gemcitabine. It reported on the development of side effects of the respiratory system (lung edema, pneumonitis, acute or adult respiratory distress syndrome). The etiology of these effects is unknown. At the first signs of pneumonitis or appearance of infiltrates in the lung gemcitabine treatment should cease.
In rare cases, the treatment of gemcitabine reported with symptoms of hemolytic-uremic syndrome. At the first sign of occurrence of microangiopathic haemolytic anemia, such as a sharp decrease in hemoglobin
in thrombocytopenia, increasing the concentration of bilirubin, serum creatinine, urea, lactate dehydrogenase or nitrogen discontinue gemcitabine. Renal dysfunction may not take place at the termination of therapy in this case, hemodialysis may be required.
The prepared solution should be stored at room temperature of not higher than 25 В° C and used within 24 hours, it should not be cooled and frozen, as this can cause crystallization.
In preparing the solution should be used remedies required when using cytotoxic drugs (mask and gloves). If during the preparation of the drug solution gets into your eyes, it can cause severe irritation. In this case, you should rinse the eyes with water immediately.
If irritation persists, consult a doctor. After contact with skin, it should be washed off with water. 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). Increasing the infusion duration and frequency of administration leads to high toxicity. Optimal mode for safe administration of gemcitabine in combination therapeutic regimens with radiotherapy have not yet been defined.
Effect on driving and operating machinery
During the treatment period, care must be taken when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor 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
Concomitant radiation therapy is additive inhibition of bone marrow function (for administration of gemcitabine at a dose of 1 g / m 2 (up to 6 weeks treatment) for the background of radiotherapy on the chest in patients with non-small cell lung cancer, had significant toxicity in the form of severe and potentially life-threatening pneumonia and esophagitis).
Immunosuppressants (azathioprine, chlorambucil, glyukokortikosteriodnye agent, cyclophosphamide, cyclosporine, mercaptopurine) increase the risk of infections.
It reduces the production of antibodies and increases the side effects associated with simultaneous use of inactivated or live virus vaccines (the interval between the application of medicaments to be from 3 to 12 months).
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug is stored in reach of children at a temperature not higher than 25 В° C without cooling and do not freeze. The prepared solution should be stored at a temperature of about 25 В° C is not more than 24 h, cooled and not frozen.
Shelf life - 3 years. Do not use after the expiration date printed on the package.
