Tolgetzit - instructions for use, doses, side effects, contraindications

Composition:1 bottle contains:
active substance: gemcitabine hydrochloride 227 mg or 1135 mg (corresponding to 200 mg or 1000 mg of gemcitabine, respectively),
Excipients: mannitol 200 mg or 1000 mg, sodium acetate trihydrate 12.50 mg or 62.50 mg.

Description:White porous lyophilizate in the form of a burrito or individual aggregates, or free powder.

Pharmacotherapeutic group:Antitumor agent - antimetabolite

ATX: & nbsp

L.01.B.C.05 Gemcitabine

Pharmacodynamics:

Gemcitabine is an antimetabolite from the group of pyrimidine analogues. It has a specific effect on the S-phase of the cell cycle and G₁/ S-phase of cell division. Activity of the drug is associated with intracellular transformation into two active metabolites - gemcitabine diphosphate and gemcitabine triphosphate. Gemcitabine diphosphate Inhibits the enzyme responsible for the catalytic synthesis of deoxynucleoside triphosphates required for DNA synthesis. Gemcitabine triphosphate competes with endogenous deoxynucleoside triphosphates for incorporation into DNA. Decreased intracellular concentration of deoxynucleoside triphosphates under the action of gemcitabine diphosphate leads to an increase in the amount of gemcitabine triphosphate in DNA, and hence to inhibition of DNA synthesis. DNA polymerase-epsilon is unable to remove gemcitabine-embedded triphosphate and cause DNA-chain repair.Gemcitabine is a powerful radiosensitizer. In studies in vitro it caused pronounced radiosensitization at concentrations that were below the cytotoxic concentrations.

Pharmacokinetics:

Distribution: the volume of distribution is significantly affected by the duration of gemcitabine infusion and the sex of the patient. With short-term infusion (<70 minutes), the volume of distribution is 50 l / m², indicating that there is no active distribution of gemcitabine in the tissues. With prolonged infusion (70-285 minutes), the volume of distribution is 370 l / m², indicating a slow leveling of the concentration in the tissue compartment.

Binding to proteins: very low (<10%).

Biotransformation: by nucleoside kinase gemcitabine is subjected to intracellular metabolism with the formation of two active metabolites (gemcitabine diphosphate and gemcitabine triphosphate); In addition, the drug is deaminated to form an inactive metabolite - uracil.

Half-life:

Short-term infusions (<70 minutes):

Women: 29 years - 49 minutes; 45 years - 57 minutes; 65 years - 73 minutes; 79 years - 94 minutes. Men: 29 years - 42 minutes; 45 years - 48 minutes; 65 years - 61 minutes; 79 years - 79 minutes. Prolonged infusions (70-285 minutes): 245-638 minutes, depending on sex and age. Metabolite gemcitabine triphosphate - terminal excretion (from peripheral blood mononuclear cells): 1.7-19.4 hours.

Excretion: by kidneys, from 92 to 98% of a single dose of the radioactive isotope gemcitabine (1000 mg / m2 body surface area, administered for 30 minutes to five patients) was excreted within one week, mainly in the form of inactive Metabolite-uracil (approximately 89% from the excreted dose) and again in the form of unchanged gemcitabine (less than 10% of the excreted dose).

Clearance depends on sex and age as follows

Women: 29 years of age: 69.4 liters per hour per square meter. meter body surface (l / h / m²); 45 years: 57 l / h / m²; 65 years: 41.5 l / h / m²; 79 years: 30.7 l / h / m².

Men: 29 years old: 92.2 l / h / m²45 years: 75.7 l / h / m²; 65 years: 55.1 l / h / m²; 79 years: 40.7 l / h / m².

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.
- Unresectable, local-recurring or metastatic breast cancer with progression after neoadjuvant and / or adjuvant therapy with anthracyclines included in the absence of contraindications to their prescription as part of combination therapy with paclitaxel.
- Locally distributed or metastatic urothelial cancer (cancer of the bladder, renal pelvis, ureters, urethra).
- Locally or metastatic ovarian cancer in combination with carboplatin in patients with progression of the disease, at least 6 months after the first line of therapy based on platinum-containing drugs.
- Locally or metastatic pancreatic cancer
- Locally or metastatic cervical cancer

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)

Carefully:With caution: with a violation of the liver and / or kidney function,oppression of bone marrow hematopoiesis (including on the background of concomitant radiation or chemotherapy), cardiovascular diseases, metastatic liver damage, hepatitis, alcoholism, concomitant radiotherapy, acute infectious diseases of viral, fungal or bacterial nature (including chickenpox encircling deprive).

Dosing and Administration:

Gemcitabine is administered intravenously drip for 30 minutes.

Non-small cell lung cancer

Monotherapy. The recommended dose of the drug is 1000 mg / m² on days 1, 8 and 15 of each 28-day cycle.

Combination therapy with cisplatin. The recommended dose of the drug is 1250 mg / m² on days 1 and 8 of each 21-day cycle or 1000 mg / m² on days 1, 8 and 15 of each 28-day cycle. Cisplatinum is administered at a dose of 70 mg / m² 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 / m² or 1200 mg / m² 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 first day of the cycle after the infusion of gemcitabine.

Mammary cancer

Combined therapy. As first-line therapy for the progression of the disease after neoadjuvant therapy, including anthracyclines.The recommended dose of the drug is 1250 mg / m² at 1 and 8 days in combination with paclitaxel, which is administered after the administration of gemcitabine at a dose of 175 mg / m² 1 day of each 21-day cycle is dripped intravenously for about 3 hours.

Urothelial cancer

Monotherapy. The recommended dose of the drug is 1250 mg / m² on days 1, 8 and 15 of each 28-day cycle.

Combined therapy. The recommended dose of the drug is 1000 mg / m² on days 1, 8 and 15 in combination with cisplatin, which is administered at a dose of 70 mg / m² immediately after the infusion of gemcitabine on or on day 2 of each 28-day cycle.

Ovarian Cancer

Monotherapy. The recommended dose of the drug is 800-1250 mg / m² on days 1, 8 and 15 of each 28-day cycle.

Combined therapy. The recommended dose of the drug is 1000 mg / m² on days 1 and 8 in combination with carboplatin in a dose of AUC (area under the concentration-time curve) of 4.0 mg / ml x min, which is injected immediately after the infusion of gemcitabine on day 1 of each 21-day cycle.

Pancreas cancer

Monotherapy. The recommended dose of the drug is 1000 mg / m² Once a week for 7 weeks followed by a weekly break. The preparation is then administered on days 1, 8 and 15 of each 28-day cycle.

Cervical cancer (locally advanced or metastatic).

Combined therapy.

With locally advanced cancer (neoadjuvant) and with metastatic cancer gemcitabine is administered at a dose of 1250 mg / m² on days 1 and 8 of each 21-day cycle. Cisplatinum is administered after the administration of gemcitabine in a dose of 70 mg / m2 per day of the cycle against a background of hyperhydration.

With locally advanced cancer with simultaneous radiotherapy gemcitabine is administered once a week for 6 weeks at a dose of 125 mg / m² with the subsequent (immediately after the introduction of gemcitabine) by the administration of cisplatin in a dose of 40 mg / m² for 1-2 hours before the start of radiotherapy. Radiation therapy is performed for 28 fractions, in a single focal dose of 1.8 Gy, 5 days a week to a total focal dose of 50.4 Gy.

Change in the dose of the drug due to hematological toxicity The onset of the treatment cycle

Regardless of the indications, before each administration of the drug, it is necessary to evaluate the concentration of platelets and granulocytes.

The condition for the initiation of treatment is the absolute number of neutrophils not less than 1500/1 μl and the number of platelets is not less than 100,000 / 1 μl.

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

The absolute amount of neutrophils (in 1 μl)		The number of platelets (in 1 μl)	% 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 / μL and platelets to 50,000 / μL, 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

The absolute amount of neutrophils (in 1 μl)		The number of platelets (in 1 μl)	% 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 reached to at least 1500 / μl and platelets to 100,000 / μL

Modification of the dose of gemcitabine, used in combination with carboplatin in the treatment of ovarian cancer.

The absolute amount of neutrophils (in 1 μl)		The number of platelets (in 1 μl)	% of the standard dose
>1500	and	≥ 100000	100
1000-<1500	or	75000-100000	50
< 1000	or	< 75000	Postpone the introduction *

The dose of gemcitabine in the next cycle should be reduced by 25% for all indications in cases when the previous cycle showed:

- Reduction of the absolute number of neutrophils <500 / μL, lasting more than 5 days

- Reducing the absolute number of neutrophils <100 / μL, lasting more than 3 days

-Febrile neutropenia

- decrease in the number of platelets <25000 / μL

The cycle was delayed more than 1 week due to hematologic toxicity

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, as 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): Gemcitabine is well tolerated by patients over 65 years of age. Specific recommendations for changing the dose of the drug for this population are absent.

Children (<18 years): gemcitabine It is not recommended to prescribe to 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 is used without preservatives.

To prepare 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. Solutions prepared with a concentration higher than 40 mg / ml may be accompanied by incomplete dissolution.

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 intravenous infusion before administration.

Before parenteral administration, it is necessary to visually monitor the prepared solution for mechanical impurities and discoloration.

Side effects:

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 "liver" transaminases (ACT, ALT), alkaline phosphatase; often - anorexia, diarrhea, constipation, stomatitis, increased bilirubin concentration; rarely - increased activity of gamma-glutamyltransferase.

From the genitourinary system: very often - hematuria and mild proteinuria; rarely - kidney failure,clinical signs and symptoms similar to hemolytic uremic syndrome (decreased hemoglobin, thrombocytopenia, increased bilirubin, creatinine, urea and / or lactate dehydrogenase activity in blood serum).

From the skin and skin appendages: very often - skin rashes, accompanied by itching, alopecia; often - skin itching, increased sweating; rarely - 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 pneumonia, 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 - flu-like syndrome, peripheral edema; often - fever, chills, asthenia, back pain, myalgia; sometimes puffiness of the face; very rarely - anaphylactic reactions.

Overdose:

The antidote for gemcitabine is unknown. With the introduction of gemcitabine in doses up to 5700 mg / m² intravenously drip for 30 minutes every two weeks, the level of toxicity of treatment remained acceptable. If suspected of an overdose of gemcitabine, the level of cytopenia should be monitored and, if necessary, maintenance therapy should be prescribed.

Interaction:Specific studies of gemcitabine interactions have not been conducted.

Radiation therapy

Concomitant radiation therapy (concomitant with the administration of gemcitabine or with an interval of <7 days before the start of treatment): in this situation, the toxicity of treatment depends on many factors, including the dose of gemcitabine and the frequency of its administration, the dose of radiation, the 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 non-small-cell lung cancer received gemcitabine in a dose of 1000 mg / m² for 6 consecutive weeks in combination with therapeutic radiation on the chest area, significant toxicity was noted, in the form of severe and potentially life-threatening inflammation of the mucosa,mainly esophagitis and pneumonitis, especially in patients with a large volume of tissue irradiation (median volume of irradiated tissue 4795 cm³). In subsequent studies, it was shown that a combination of lower doses of gemcitabine and radiation therapy is better tolerated by patients and is characterized by a predictable toxicity profile. Thus, in one of the Phase II studies, patients with non-small cell lung cancer underwent radiation therapy at a dose of 60 Gy together with the administration of gemcitabine (600 mg / m² 4 times) and cisplatin (80 mg / m² 2 times) for 6 weeks.

Sequential therapy (break> 7 days): according to existing data, the introduction of gemcitabine more than 7 days before the start of radiation therapy or more than 7 days after it is completed is not accompanied by an increase in toxicity of treatment, with the exception of skin lesions associated with the administration of chemotherapy after irradiation . Treatment with gemcitabine can be started 7 days after irradiation or after resolution of all acute radiation reactions.

As with concomitant or sequential use of gemcitabine and radiation therapy may radiation injury irradiated tissue (eg., Esophagitis, colitis and pneumonia).

Other types of interaction

With simultaneous administration with live viral vaccines, it is possible to intensify the process of replication of the vaccine virus, increase its side / adverse effects and / or reduce the production of antibodies in the patient's body in response to the introduction of the vaccine.

Incompatibility

Studies of the compatibility of gemcitabine were not conducted. To mix gemcitabine with other medicinal products is not recommended.

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.
When signs of adverse events of the respiratory system (eg., Pulmonary edema, interstitial pneumonitis or adult respiratory distress syndrome), on treatment with gemcitabine treatment should cease and prescribe appropriate therapy.
At the first signs of microangiopathic hemolytic anemia, such as a rapid reduction in the concentration of hemoglobin with accompanying thrombocytopenia, increased serum bilirubin, creatinine, urea nitrogen, or increase the activity of lactate dehydrogenase (LDH), gemcitabine should be canceled. 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 therapy with gemcitabine should use reliable methods of contraception. For men receiving gemcitabine, it is recommended to resort to cryopreservation of sperm before the start of treatment due to the risk of infertility caused by the use of this drug.

Effect on the ability to drive transp. cf. and fur:Data on the effect of gemcitabine therapy on the ability to drive a vehicle and work with mechanisms are not available, however, some side effects of the drug, such as increased drowsiness, can adversely affect the ability to drive and perform potentially dangerous activities requiring increased concentration and speed of psychomotor reactions .

Form release / dosage:Lyophilizate for the preparation of a solution for infusions of 200 mg, 1000 mg.

Packaging:200 mg or 1000 mg gemcitabine is placed in vials of 15 ml or 50 ml capacity from colorless glass, sealed with a rubber stopper, covered with an aluminum cap with a colored plastic lid. 1 bottle in a plastic pallet along with instructions for use in a cardboard bundle.

Storage conditions:At a temperature of 15 ° C to 30 ° C. The prepared solution should be stored at a temperature of 23 ° C to 27 ° C for 24 hours; Do not freeze.
Keep out of the reach of children!

Shelf life:2 years.
Do not use after expiry date!

Terms of leave from pharmacies:On prescription

Registration number:LP-001712

Date of registration:18.05.2012

The owner of the registration certificate:Tolmar, Corp.Tolmar, Corp. Panama

Manufacturer: & nbsp

FARMACEUTICA PARAGUAYA, S.A. Paraguay

Information update date: & nbsp2015-12-15

Illustrated instructions

Instructions

Tolgette (Tolgecit)