Composition, form of production and packaging
Liofilizate for the preparation of a solution for infusions from white to almost white.
1 f.
gemcitabine hydrochloride 228 mg,
which corresponds to the content of gemcitabine 200 mg
Excipients: mannitol - 200 mg, sodium acetate - 12.5 mg.
Glass bottles (1) - cardboard packs.
Liofilizate for the preparation of a solution for infusions from white to almost white.
1 f.
gemcitabine hydrochloride 1.14 g,
which corresponds to the content of gemcitabine 1 g
Excipients: mannitol - 1000 mg, sodium acetate - 62.5 mg.
Glass bottles (1) - cardboard packs.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2014.
PHARMACHOLOGIC EFFECT
Antitumor drug, antimetabolite group analogues of pyrimidine. The drug exhibits cyclospecificity, acting on cells in the S phase (replication phase) and G 1 / S (the gap between the initial growth phase and the replication phase).
Gemcitabine is metabolized within the cell by the action of nucleoside kinases with the formation of active diphosphate and triphosphate nucleosides. Diphosphate nucleosides inhibit ribonucleotide reductase, which acts as the only reaction catalyst leading to the formation of deoxynucleoside triphosphates required for DNA synthesis. Triphosphate nucleosides actively compete with deoxycytidine triphosphate for incorporation into DNA and RNA molecules. After integrating the intracellular metabolites of gemcitabine into the DNA strand, another additional nucleotide is added to its growing strands, which leads to complete inhibition of further DNA synthesis and programmed cell death, known as apoptosis.
PHARMACOKINETICS
Distribution
Binding to plasma proteins is negligible.
Excretion
T 1/2 ranges from 32 to 94 minutes. 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 dose administered intravenously is detected in the urine unchanged.
The system clearance varies from 30 to 90 l / h / m 2 .
Pharmacokinetics in special clinical cases
Analysis of pharmacokinetic studies with a single and repeated administration of the drug shows that V d is largely dependent on sex.
Systemic clearance, which ranges from about 30 l / h / m 2 to 90 l / h / m 2 , depends on sex and age.
INDICATIONS
- locally advanced or metastatic non-small cell lung cancer - as first-line therapy in combination with cisplatin or carboplatin, and as monotherapy in elderly patients with a functional status of 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 use;
- Locally distributed or metastatic urothelial cancer (cancer of the bladder, renal pelvis, ureter, urethra);
- locally advanced 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 derivatives;
- locally advanced or metastatic pancreatic cancer;
- locally advanced or metastatic cervical cancer;
- Cancer of the biliary tract.
The efficacy of gemcitabine in disseminated small-cell lung cancer and advanced refractory testicular cancer is shown.
DOSING MODE
Gemzar В® is injected intravenously into the drip for 30 minutes.
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.
Non-small cell lung cancer (locally advanced or metastatic), first-line therapy
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 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 mg / m 2 per day of the cycle after gemcitabine infusion against hyperhydration.
Combination therapy with carboplatin: the recommended dose of the drug is 1000 mg / m 2 or 1200 mg / m 2 on days 1 and 8 of each 21-day cycle.
Carboplatin is administered from the AUC calculation of 5.0 mg / ml / min on day 1 of the cycle after the infusion of gemcitabine.
Breast cancer (unresectable, local-recurring or metastatic)
Combination therapy with paclitaxel: as first-line therapy for the progression of the disease after neoadjuvant and / or adjuvant therapy, including anthracyclines in the absence of contraindications to them. Paclitaxel is administered at a dose of 175 mg / m 2 IV drip for 3 hours on day 1 of the 21-day cycle followed by gemcitabine. The recommended dose of the drug is 1250 mg / m 2 on days 1 and 8 of each 21-day cycle.
Before the start of combination therapy (gemcitabine + paclitaxel), the absolute number of granulocytes in the blood should be at least 1500 / Ојl.
Urothelial cancer (bladder cancer (locally advanced, metastatic and superficial), renal pelvis, ureter, urethra)
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 with cisplatin: 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 . Clinical studies have shown that with a dose of cisplatin 100 mg / m 2 , more pronounced myelosuppression is observed.
Epithelial ovarian cancer (locally advanced or metastatic, resistant to platinum derivatives)
Monotherapy: the recommended dose of the drug is 800-1250 mg / m 2 at 1, 8 and 15 days of each 28-day cycle.
Combination therapy with carboplatin: the recommended dose of the drug is 1000 mg / m 2 on days 1 and 8 in combination with carboplatin at the rate of AUC of 4 mg / ml / min, which is injected immediately after the infusion of gemcitabine on day 1 of each 21-day cycle.
Pancreatic cancer (locally advanced or metastatic, including resistant to 5-fluorouracil therapy)
Monotherapy: the recommended dose of the drug is 1000 mg / m 2 once a week for 7 weeks, followed by a weekly break. The drug is then administered on days 1, 8 and 15 of each 28-day cycle.
Cervical cancer (locally advanced or metastatic)
Combined therapy with cisplatin: with locally advanced cancer with sequential chemoradiotherapy (neoadjuvant) and with metastatic cancer, cisplatin is administered at a dose of 70 mg / m 2 on the first day of the cycle against hyperhydration followed by gemcitabine. Gemcitabine is administered at a dose of 1250 mg / m 2 at 1 and 8 days of each 21-day cycle.
In locally advanced cancer with simultaneous chemoradiotherapy, cisplatin is administered at a dose of 40 mg / m 2 , followed by (immediately after the introduction of cisplatin) by the administration of gemcitabine. Gemcitabine is administered once a week 1-2 hours before the start of radiotherapy at a dose of 125 mg / m 2 .
Bile duct cancer
Combination therapy with cisplatin: cisplatin is administered at a dose of 70 mg / m 2 per day of the cycle against a background of hyperhydration followed by gemcitabine. Gemcitabine is administered at a dose of 1250 mg / m 2 at 1 and 8 days of each 21-day cycle.
Correction of dose
In case of development of hematological toxicity, the dose of gemcitabine can be reduced, or its administration postponed in accordance with the following schemes:
A. Correction of the dose of gemcitabine within the cycle for urothelial cancer, non-small cell lung cancer, pancreatic cancer as monotherapy or in combination with cisplatin.
Absolute number of granulocytes (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
B. Correction of the dose of gemcitabine within the cycle for breast cancer in combination with paclitaxel.
Absolute number of granulocytes (in 1 Ојl) Number of platelets (in 1 Ојl) % of previous 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
B. Correction of the dose of gemcitabine within the cycle for ovarian cancer in combination with carboplatin.
Absolute number of granulocytes (in 1 Ојl) Number of platelets (in 1 Ојl) % of previous dose
> 1500 and? 100 000 100
1000-1500 or 75 000 -100 000 50
<1000 or <75 000 Postpone the introduction
To detect non-hematologic toxicity , a regular examination of the patient and control of the liver and kidneys should be carried out. Depending on the degree of toxicity, the dose can be reduced during each cycle or with the onset of a new cycle stepwise.
The drug should be delayed until, according to the doctor, toxicity is not resolved.
Special patient groups
There is no evidence to suggest that dose adjustment is required in elderly patients .
With caution, gemcitabine should be used in patients with hepatic insufficiency or impaired renal function . There is no sufficient data on the use of the drug in this category of patients. Renal failure of mild to moderate severity (GFR from 30 ml / min to 80 ml / min) does not have a significant effect on the pharmacokinetics of gemcitabine.
Gemcitabine was studied in limited studies of 1 and 2 phases in children with different types of neoplasms. The data of these studies are not enough to prove the effectiveness and safety of gemcitabine in children.
Rules for the preparation of a solution for infusions
As a solvent, only 0.9% solution of sodium chloride is used (without preservatives).
For the preparation of a solution for infusions, the contents of the 200 mg bottle are dissolved in not less than 5 ml, and 1 g in not less than 25 ml of 0.9% sodium chloride solution 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. In solutions prepared with a concentration of more than 40 mg / ml, incomplete dissolution is possible.
A prepared gemcitabine solution containing the desired dose of the drug is diluted with 0.9% sodium chloride solution for injection in an amount sufficient to conduct a 30-minute IV infusion prior to administration.
Before parenteral administration, it is necessary to visually monitor the prepared solution for mechanical impurities and discoloration.
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%).
From the hemopoietic system: very often - anemia, leukopenia, thrombocytopenia; often - febrile neutropenia; very rarely - thrombocytosis.
From the metabolism: often - anorexia.
From the nervous system: often - headache, sleep disturbance, drowsiness.
From the cardiovascular system: very often - swelling, peripheral edema; infrequently - heart failure, arrhythmia, predominantly supraventricular; rarely - myocardial infarction, lowering blood pressure.
From the respiratory system: very often - shortness of breath; often - cough, rhinitis; infrequently - bronchospasm.
From the digestive system: very often - a violation of the liver (usually mild, rarely requiring discontinuation of treatment), nausea, vomiting; often - diarrhea, stomatitis, constipation.
From the skin and subcutaneous tissues: very often - mild rash, accompanied by itching, alopecia (usually minimal hair loss); often - itching, sweating; rarely - ulcers, the formation of vesicles.
From the side of the urinary system: very often - mild proteinuria and hematuria.
From the musculoskeletal system: often - back pain, myalgia.
Allergic reactions: very rarely - anaphylactoid reactions, anaphylactic reaction.
Other: very often - flu-like syndrome (fever, headache, chills, asthenia, malaise); rarely - reactions at the injection site. The increase in body temperature and asthenia are often recorded as individual symptoms. Radiation toxicity was rarely reported.
Post-marketing data
From the side of the cardiovascular system: infrequently - heart failure, arrhythmia, mainly supraventricular; rarely - gangrene and peripheral vasculitis; very rarely - the syndrome of increased permeability of capillaries.
On the part of the respiratory system: infrequently - interstitial pneumonitis; rarely - adult respiratory distress syndrome, pulmonary edema. With the development of such effects, consideration should be given to discontinuing gemcitabine therapy. Early maintenance therapy can improve the situation.
From the side of the digestive system: very rarely - ischemic colitis.
From the skin and subcutaneous tissues: rarely - severe skin reactions, including desquamation and bullous skin lesions.
From the urinary system: infrequently - haemolytic-uremic syndrome. At the first signs of any manifestations of microangiopathic hemolytic anemia (eg, a sharp decrease in hemoglobin with concomitant thrombocytopenia, increased bilirubin, serum creatinine, urea or LDH), gemcitabine therapy should be discontinued immediately. Renal failure may be irreversible even after discontinuation of therapy and dialysis may be required.
From the liver and bile ducts: very often - an increase in the activity of liver enzymes: ACT, ALT, APF; often - increased bilirubin concentration; infrequently - severe hepatotoxicity, including hepatic impairment; rarely - increase in GGT activity.
Other: very rarely - Lyell's syndrome, Stevens-Johnson syndrome; ray reactions were recorded.
CONTRAINDICATIONS
- age up to 18 years;
- Pregnancy;
- the period of lactation (breastfeeding);
- Hypersensitivity to gemcitabine or other components of the drug.
With caution appoint a drug in violation of liver and / or kidney function, oppression of bone marrow hematopoiesis (including against the background of concomitant radiation or chemotherapy), acute infectious diseases of viral, fungal or bacterial nature.
PREGNANCY AND LACTATION
The drug is contraindicated in pregnancy and lactation (breastfeeding).
APPLICATION FOR FUNCTIONS OF THE LIVER
With caution appoint a drug for impaired renal function.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
With caution appoint a drug in case of a violation of the liver.
APPLICATION FOR CHILDREN
Gemcitabine was studied in limited studies of 1 and 2 phases in children with different types of neoplasms. The data of these studies are not enough to prove the effectiveness and safety of gemcitabine in children.
APPLICATION IN ELDERLY PATIENTS
There is no data to suggest that older people need to adjust the dose.
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.
It is necessary to conduct regular examination of the patient and assess the function of the kidneys and liver. 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.
Increasing the duration of infusion and the frequency of administration leads to an increase in toxicity.
Gemcitabine can inhibit bone marrow activity, which is manifested by leukopenia, thrombocytopenia, or anemia.
The syndrome of increased permeability of capillaries with potentially serious consequences was observed in patients who received gemcitabine as a monotherapy or in combination with other chemotherapeutic drugs. In case of the development of the syndrome of increased permeability of capillaries during therapy, it is necessary to stop treatment with gemcitabine and take the necessary measures. According to some published data, the syndrome of increased capillary permeability was associated with adult respiratory distress syndrome.
Depending on the degree of toxicity, the dose can be reduced during each cycle or with the onset of a new cycle stepwise.
Impact on the ability to drive vehicles and manage mechanisms
Studies of the effects of gemcitabine on the ability to drive motor vehicles and other mechanisms have not been conducted. Nevertheless, it is known that gemcitabine can cause drowsiness from mild to moderate severity, especially when taken with alcohol.
Patients should be cautioned against controlling the mechanisms when they feel drowsy.
OVERDOSE
Treatment: antidote is not known. Clinically tolerable toxicity was observed with single doses up to 5.7 g / m 2 IV for 30 min every 2 weeks. In case of suspected overdose, the patient should be under constant medical supervision, including counting the blood formula. If necessary, perform symptomatic treatment.
DRUG INTERACTION
Radiation therapy
Simultaneous application (joint or with an interval less than 7 days): the toxicity of the conjugate with multimodal treatment depends on many different factors: gemcitabine dose, frequency of administration of gemcitabine dose radiation therapy, radiation therapy planning technique, the type and amount of the irradiated tissue. Preclinical and clinical studies have shown that gemcitabine has radiosensitizing effect. In the only study in which gemcitabine was administered at a dose of 1000 mg / m 2for 6 weeks in conjunction with radiation therapy of the chest in patients with non-small cell lung cancer, it was detected 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 irradiation volume 4795 cm 3 ). Conducted later study (study II phase with small cell lung cancer) indicate the advisability of administration of gemcitabine at lower doses with concomitant radiotherapy with predicted toxicity. Radiation therapy to the chest (ODS 66 Gy) was performed simultaneously with gemcitabine chemotherapy in a dose of 600 mg / m 2 (4 injections) and cisplatin at a dose of 80 mg / m2 (2 injection) for 6 weeks. Several studies phases I and II showed that for small cell lung cancer and pancreatic cancer expedient gemcitabine monotherapy (at a dose of 300 mg / m 2 / week) in parallel with radiotherapy. Optimal for safe administration of gemcitabine with therapeutic doses of radiation therapy has not yet been set for all types of tumors.
Sequential use (more than 7 days interval): a radiation reaction with gemcitabine administered more than 7 days before or after radiation therapy, increased toxicity have been reported. These data suggest that gemcitabine can be administered one week after radiation therapy or after will be eliminated acute effects of radiation therapy. And at the same time, and consistent application of gemcitabine with radiation therapy have been reported ray irradiated tissue damage (e.g., esophagitis, colitis and pneumonia).
Other
We do not recommend joint application with live vaccines Yellow fever and other live vaccines, due to the risk of systemic disease which can be fatal, particularly in immunosuppressed patients.
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 15 В° to 30 В° C. Shelf life - 3 years.
The prepared solution should be stored at a temperature of from 15 В° to 30 В° C for up to 24 hours.
