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

Antitumor agent, antimetabolite of the group of pyrimidine analogs, suppresses the synthesis of DNA. It exhibits cyclospecificity by acting on cells in phases S and G1 / S. 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). 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 radiosensitizing agent even in concentrations lower than cytotoxic.

Pharmacokinetics:

The maximum plasma concentration of gemcitabine (from 3.2 μg / ml to 45.5 μg / ml) is reached 5 minutes after the end of the infusion. Pharmacokinetic analysis of studies with single and multiple doses shows that the volume of distribution is largely dependent on sex. The binding of gemcitabine to plasma proteins is negligible.

In organism gemcitabine rapidly metabolized by cytidine deaminase in the liver, kidneys, blood and other tissues, resulting in the formation of gemcitabine mono-, di- and triphosphates (dTdCMP, dFdCDP and dFdCTP), of which active are considered dFdCDP and dFdCTP.

Gemcitabine is rapidly excreted from the body with urine mainly as an inactive metabolite of 2 '-deoxy-2', 2 '-difluorouridine. Less than 10% of the intravenous dose is detected in the urine in the form of an unchanged drug. System clearance, which ranges from about 30 l / h / m² up to 90 l / h / m², depends on age and sex.

The half-life period ranges from 42 minutes to 94 minutes. Subject to compliance the recommended dosage regimen, the complete excretion of gemcitabine occurs within 5-11 hours from the onset of 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.

- Unresectable, local-recurring or metastatic breast cancer after neoadjuvant and / or adjuvant therapy with anthracyclines 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 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 or metastatic pancreatic cancer.

- Locally or metastatic cervical cancer.

Gemcitabine in monotherapy or in combination with other antitumor agents is active in progressive small cell lung cancer, progressive recurrent testicular cancer and bile duct 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:

If the liver and / or kidney function is impaired, bone marrow hematopoiesis is suppressed (including on the background of concomitant radiation or chemotherapy), cardiovascular diseases,with metastatic liver damage, hepatitis, alcoholism, with simultaneous radiotherapy, acute infectious diseases of viral, fungal or bacterial nature (including chicken pox, shingles).

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 pisaplatin: 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 in a dose 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.

Urothelial 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 1 st and 8 th days in combination with carboplatin in a dose AUC 4.0 mg / ml * min, which is injected immediately after the infusion of gemcitabine on the 1st day of each 21-day cycle.

Pancreas cancer

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 1st, 8th and 15th days 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 in the 1st and 8th days of each 21-day cycle. Cisplatinum is administered after administration of gemcitabine at a dose of 70 mg / m² in the first 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 in connection with the phenomena 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 / μL and a platelet count of at least 100,000 / 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 performed 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 *

* 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

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

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

-Febrile neutropenia

decrease in the number of platelets <25,000 / 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

Patents with impaired liver and kidney function: use gemcitabine in patients with hepatic insufficiency or with impaired renal function should be taken with caution, since 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 pet): gemcitabine well tolerated by patients older than 65 years. 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 at least 5 ml, and 1 g in at least 25 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 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; frequent febrile neutropenia; very rarely - thrombocytosis.

On the part of the digestive system: very often - nausea, vomiting, increased activity of "liver" transaminases (aspartate aminotransferase, alanine aminotransferase), 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 - renalinsufficiency, clinical signs and symptoms similar to hemolytic uremic syndrome (decreased hemoglobin, thrombocytopenia, increased levels of bilirubin, creatinine, urea and / or lactate dehydrogenase in the 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 2 weeks, the level of toxicity of treatment remained acceptable. If suspected of an overdose of gemcitabine, the degree 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 mucous membrane, mainly esophagitis and pneumonitis, especially in patients with a large volume of tissue irradiation (median volume irradiated fabric 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 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 / m² 4 times) and cisplatin (80 mg / m² 2 times) 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. 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 replication process of the vaccine virus,increasing its adverse / adverse effects and / or reducing 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:

Note:

After dilution, the drug retains chemical and physical stability for 28 days at a temperature of 2-8 ° C and at room temperature in a glucose solution of 5% or a solution of sodium chloride 0.9% (0.1 mg / ml and 7.5 mg / ml ). From the microbiological point of view, the prepared preparation should be used immediately. In other cases, the drug can be stored for no more than 24 hours at a temperature of 2-8 ° C, unless dilution has been carried out under approved aseptic conditions.

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

Packaging:

Vials, packs cardboard.

Storage conditions:In the dark place at a temperature of no higher than 25 ºC.

Shelf life:

2 years.

Terms of leave from pharmacies:On prescription

Registration number:LSR-008341/10

Date of registration:18.08.2010 / 03.07.2014

Expiration Date:Unlimited

The owner of the registration certificate:ARS, LLC ARS, LLC Russia

Manufacturer: & nbsp

VMG Pharmaceuticals, Private Ltd. India

Representation: & nbspARS, LLCARS, LLC

Information update date: & nbsp21.03.2017

Illustrated instructions

Instructions

Gemcitabine (Gemcitabine)