Gemcitabine-Rus - instructions for use, dose, side effects, contraindications

Pharmacodynamics:Antitumor agent, antimetabolite of the group of pyrimidine analogs, suppresses the synthesis of DNA. It exhibits cyclospecificity, acting on cells in the S and G1 / S phases. It is metabolized in the cell by the action of nucleosid 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). 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). When gemcitabine is combined with cisplatin, the effectiveness of treatment is increased to 69%. Gemcitabine is also a strong radiosensitizing agent even at concentrations lower than cytotoxic.

Pharmacokinetics:TCmax in plasma after a single infusion with a duration of 30 minutes dose of 1 g / m 2 - 3-15 min; the therapeutic concentration of nucleosides in plasma (4-5 μg / ml) persists for 1.5 hours. The connection with plasma proteins is low (less than 10%). The volume of distribution depends significantly on the duration of infusion and sex: for short-term infusion (less than 70 min) - 50 l / sq. M, with a long infusion (70-285 min) - 370 l / sq. M (slower equilibrium in tissue compartment). Metabolized in cells of the liver, kidneys, blood enzyme cytidine deaminase in stages, until the formation of an inactive metabolite of 2'-deoxy-2 ', 2'-difluoruridine. The intracellular concentration of nucleosides is directly proportional to the plasma content (when the concentration in the plasma exceeds 5 μg / ml, the intracellular concentration of nucleosides no longer increases). T1 / 2 depends on the duration of the infusion, sex and age: for short-term infusions (less than 70 min) in women aged 29 years - 49 min, 45 years - 57 min, 65 years - 73 min, 79 years - 94 min; for men aged 29 years - 42 minutes, 45 years - 48 minutes, 65 years - 61 minutes, 79 years - 79 minutes; with prolonged infusions (70-285 min) - 245-638 min, depending on sex and age. Intracellular metabolites in plasma and urine are not detected.Systemic clearance varies from 0.5 to 1.5 l / min / sq. M and depends on age and sex. In women, the clearance of the drug is somewhat lower than that of men. It is mainly excreted by the kidneys in the form of an inactive metabolite of uracil (89%), and also unchanged (less than 10%); less than 1% - with calves. Age and gender have a significant effect on the clearance of the drug: in women aged 29, it is - 1150 ml / h / m 2, 45 years - 950 ml / h / m, 65 years -691.7 ml / h / m, 79 years - 511.7 ml / h / m 2; in men aged 29 years - 1536.7 ml / h / m, 45 years - 1261.7 ml / h / m, 65 years - 918.3 ml / h / m, 79 years - 678.3 ml / h / sq. m. m. With a reduced function of the kidneys in the body can accumulate inactive metabolite.

Indications:

- Locally 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 or metastatic urothelial cancer (cancer of the bladder, renal pelvis, ureters, urethra).

- Locally or metastatic epithelial ovarian cancer as a motor therapy or in combination with carboplatin in patients with progression of the disease after the first line of therapy based on platinum-containing drugs.

- Locally or metastatic pancreatic cancer.

Contraindications:Hypersensitivity, pregnancy, lactation, children's age.

Carefully:With hepatic insufficiency, 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), with cardiovascular diseases, cardiovascular diseases in anamnesis, with metastatic liver damage, hepatitis, alcoholism, with simultaneous radiotherapy.

Dosing and Administration:

Gemcitabine-Rus 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 (area under the concentration-time curve) 5.0 mg / ml * min on the 1st day of the cycle after the infusion of gemcitabine.

Mammary cancer.

Combination therapy: as 1st line therapy for disease progression after neoadjuvant therapy, including anthracyclines, the recommended dose of the drug is 1250 mg / m² on the 1 st and 8 th days in combination with paclitaxel, which is administered after the administration of gemcitabine at a dose of 175 mg / m² on the 1st day of each 21-day cycle, intravenously drip for about 3 hours.

Orthotal cancer.

Monotherapy: the recommended dose of the drug is 1250 mg / m² on days 1, 8 and 15 of each 28-day cycle. Combination therapy: the recommended dose of the drug is 1000 mg / m² in the 1 st, 8 th and 15 th days in combination with cisplatin, which is administered at a dose of 70 mg / m² immediately after the infusion of gemcitabine on the 1st or 2nd day of each 28-day cycle. Epithelial ovarian cancer.

Monotherapy: the recommended dose of the drug is 800-1250 mg / m² in the 1st, 8th and 15th days of each 28-day cycle. Combination therapy: the recommended dose of the drug is 1000 mg / m² in the 1st and 8th days in combination with carboplatin in a dose of AUC 4.0 mg / ml * min, which is administered immediately after the infusion of gemcitabine on the 1 st day of each 21-day cycle.

Cancer of the pancreas feels.

Monotherapy: the recommended dose of the drug is 1000 mg / m² 1 time per week for 7 weeks followed by a one-week break. Then the drug is administered on the 1 st, 8 th and 15 th days of each 28-day cycleIn case of development of hematological toxicity, the dose of gemcitabine can be reduced or its administration postponed in accordance with the following scheme: if the number of granulocytes is more than 1 thousand / μl and platelets more than 100 thousand / μl use the full recommended dose; with a granulocyte count of 0.5-1 thousand / μL or platelets of 50-100 thousand / μL, the dose is reduced to 75% of the recommended dose; if the number of granulocytes is less than 500 / μL or platelets less than 50 thousand / μL, the introduction is postponed.

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.

The absolute amount of neutrophils (in 1 μl)	The number of platelets (in 1 μl)	% of previous dose
> 1000	and> 100 000	100
500-1000	or 50 000-100	75
	000
<500	or <50 000	Postpone
		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 glands.

The absolute amount of neutrophils (in 1 μl)		The number of platelets (in 1 μl)	% 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 Introduction *

* Treatment within the cycle is not resumed.

The next introduction of gemcitabine is carried out on the first day the next cycle when the number of neutrophils is restored 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 previous dose
> 1500	and	≥ 100 000	100
1000-1500	or	75 000-100 000	50
<1000	or	<75 000	Postpone 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 / μl and platelets to 100,000 / μL. The dose of gemcitabine in the next cycle should be reduced by 25% for all indications in cases when the previous cycle showed:

- Reducing 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, a decrease in the number of platelets <25000 / μL,

-cycle was delayed more than 1 week due to hematologic toxicity. To detect non-hematologic toxicity, regular examination of the patient and control of liver and kidney function 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 decision to delay the next injection of the drug should be based on a clinical assessment by the doctor of the toxicity dynamics.Do not change the dosage regimen in patients older than 65 years. Rules for preparation of infusion solution: solvent - 0.9% solution NaCl for injections without preservatives. To dissolve 200 mg of gemcitabine in the bottle, add at least 5 ml of solvent, to dissolve 1 g - at least 25 ml of the solvent and shake until completely dissolved.The maximum concentration of gemcitabine should not exceed 40 mg / ml. A prepared solution containing the desired dose of the preparation is diluted with sufficient solvent before administration for 30 minutes of IV infusion.Before the introduction, it should be ensured that there are no suspended particles in the solution.

Side effects:

From the nervous system:headache, drowsiness, insomnia.

From the respiratory system: dyspnea, cough, rhinitis, bronchospasm, interstitial pneumonia, pulmonary edema, acute respiratory distress syndrome.

From the cardiovascular system: decrease in blood pressure, myocardial infarction, heart failure, arrhythmias.

From the hematopoiesis: leukopenia, thrombocytopenia, anemia; rarely - thrombocytosis.

From the digestive system: nausea, vomiting, constipation or diarrhea, stomatitis, hyperbilirubinemia, increased activity of "hepatic" transaminases, alkaline phosphatase, anorexia, ischemic colitis, toxic liver damage, including hepatic insufficiency with fatal outcome.

From the urinary system: proteinuria, hematuria; rarely - renal failure, hemolyticcouremic syndrome (decrease in Hb, thrombocytopenia, hyperbilirubinemia, hypercreatininemia, increased lactate dehydrogenase activity and urea concentration).

From the skin: rash, pruritus, alopecia, excessive sweating, ulceration, blistering, severe skin reactions, including desquamation and bullous eruptions; Lyell's syndrome, Stevens-Johnson syndrome.

Other: flu-like syndrome, peripheral edema, hyperthermia, chills, back pain, myalgia, facial puffiness, anaphylactic reactions.

Overdose:

Symptoms: myelodepression, anemia (excessive fatigue or weakness), leukopenia, neutropenia, infection (chills, cough, hoarseness, pain in the side or lower back, painful or difficult urination), thrombocytopenia (bleeding, hemorrhage, black tar, feces in urine and feces , ecchymosis), paresthesia, a pronounced skin rash.

Treatment: in the case of suspected overdose, the patient should be under constant medical supervision, including the calculation of the blood formula, if necessary, an asymptomatic treatment. The antidote is unknown.

Interaction:

Specific studies of gemcitabine interactions have not been conducted. Concomitant radiation therapy (concomitant with the administration of gemcitabine or with an interval of <7 days before the start of treatment): in this situation, toxicitytreatment 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 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). 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 phase II study, patients with non-small cell lung cancer received radiation therapy at a dose of 60 g along 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 administration of gemcitabine more than 7 days before the start of 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. Treatment with gemcitabine can be started 7 days after irradiation or after resolution of all acute radiation reactions. As with concomitant, and with the consistent use of gemcitabine and radiation therapy, radiation damage to irradiated tissues is possible (for example, esophagitis, colitis and pneumonitis). Immunosuppressants (azathioprine, chlorambucil, glucocorticosteroids, cyclophosphamide, ciclosporin, mercaptopurine) increase the risk of infection. With simultaneous application 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. Therefore, because of the risk of systemic, possibly lethal complications, especially in patients with a decreased immune status, the interval between the use of gemcitabine and such vaccines should be at least 3 months or more (up to 12 months), depending on the patient's immune status.

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. 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.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), when treatment with gemcitabine treatment should be stopped and appropriate therapy is 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, urea nitrogen, or an increase in lactate dehydrogenase activity, gemcitabine should be canceled. Increasing the duration of infusion and the frequency of administration leads to an increase in toxicity. The risk of skin reactions increases in the presence of radiation therapy in history. 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 end of gemcitabine therapy, reliable contraceptive methods should be used. 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.

In the treatment of patients on a controlled sodium diet should take into account the content in the preparation of sodium in the following amounts: a bottle of 200 mg of the drug Gemcitabine-RUS contains 12.5 mg (<1 mmol) of sodium, the bottle of 1000 mg of the drug Gemcitabine-RUS contains 62.5 mg (<1 mmol) of sodium.

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

Storage conditions:

In a dry, the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-002152

Date of registration:19.07.2013 / 27.01.2014

Expiration Date:19.07.2018

The owner of the registration certificate:MANAS MED, LTD MANAS MED, LTD Russia

Manufacturer: & nbsp

RUS-MED EXPORTS, Pvt. Ltd. India

Representation: & nbspManas Med, OOOManas Med, OOO

Information update date: & nbsp22.03.2017

Illustrated instructions

Instructions

Gemcitabine-Rus (Gemcitabine-Rus)