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

active substance - gemcitabine hydrochloride 228.0 mg (in terms of gemcitabine 200.0 mg); Excipients - mannitol 200.0 mg, sodium acetate trihydrate 15.0 mg, sodium hydroxide 0.6 mg.

1 bottle of 1000 mg contains

active substance - gemcitabine hydrochloride 1140.0 mg (in terms of gemcitabine 1000.0 mg); Excipients - mannitol 1000.0 mg, sodium acetate trihydrate 75.0 mg, sodium hydroxide 3.0 mg.

Description:White lyophilized dried mass.

Pharmacotherapeutic group:Antitumour agent, antimetabolite

ATX: & nbsp

L.01.B.C.05 Gemcitabine

Pharmacodynamics:

Antitumor drug, antimetabolite, analogue of pyrimidine. Is a prodrug, the active form is converted, metabolized in a tumor cell by the action of nucleoside kinases to active diphosphate and triphosphate nucleosides. Gemcitabine diphosphate inhibits ribonucleotide reductase. Gemcitabine triphosphate is embedded in DNA (to a lesser extent in RNA), which leads to the cessation of further DNA synthesis and programmed cell lysis (apoptosis); while DNA repair is not possible. In T-lymphoblastic cells gemcitabine induces internucleosomal DNA fragmentation, which is one of the factors that program cell death.

Has a phase specificity of action: it stops the vital activity of cells in the S-phase and blocks the tumor progression of cells on the boundary of the phases G₁ and S.

Gemcitabine exhibits a strong radiosensitizing property at concentrations lower than cytotoxic.

Pharmacokinetics:

The time to reach the maximum concentration in the plasma after a single infusion of 30 min dose of 1000 mg / m² is 3-15 minutes. The connection with plasma proteins is low (less than 10%). The therapeutic concentration of nucleosides in plasma (4-5 μg / ml) persists for 1.5 hours. The half-life (T₁_/2), volume of distribution (Vd) and systemic clearance are linear depending on the duration of infusion and the age of the patient. Among women T_1/2more (49-94 min) than in men (42-79 min). The system clearance varies from 0.5 to 1.5 l / min / m². In women, the clearance of the drug is somewhat lower than that of men. 1t of the terminal phase of the active metabolite (from peripheral blood mononuclear cells) is 1.7-19.4 hours. Metabolized in the cells of the liver, kidneys, blood by the enzyme cytidine deaminase step-by-step until the formation of an inactive metabolite of 2'-deoxy-2 ', 2'-difluororidine (uracil).The maximum concentration in the blood (C_max) of this metabolite is achieved 30 minutes after the infusion. The intracellular concentration of nucleosides is directly proportional to the plasma content, but when the concentration in the plasma exceeds 5 μg / ml, the intracellular concentration of nucleosides no longer increases. 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% is excreted with calories.

Moderate or moderate severity of renal failure (glomerular filtration rate from 30 ml / min to 80 ml / min) has no significant effect on the pharmacokinetics of gemcitabine. With a reduced function of the kidneys in the body can accumulate inactive metabolite.

Indications:

- locally advanced or metastatic non-small cell lung cancer (as first-line therapy in combination with cisplatin, in monotherapy in elderly patients with a functional status on the ECOG-WHO scale of 2);

- inoperable local-recurring or metastatic breast cancer (in monotherapy with progression of the disease after first-line therapy,including anthracyclines; in the combination therapy with paclitaxel after neoadjuvant and / or adjuvant therapy with the inclusion of anthracyclines in the absence of contraindications to their use);

- Locally distributed or metastatic urothelial cancer (cancer of the bladder, renal pelvis, ureters, urethra), (in monotherapy or in combination with cisplatin);

- Locally spread or metastatic ovarian cancer (monotherapy or in combination with carboplatin in patients with progression of the disease after the first line of therapy based on platinum compounds);

- Locally spread or metastatic pancreatic cancer (monotherapy);

- Locally advanced or metastatic cervical cancer (in combination with cisplatin).

Contraindications:Hypersensitivity to gemcitabine or other components of the drug, pregnancy, lactation, children's age (efficacy and safety not determined).

Carefully:Hepatic insufficiency, hepatitis, metastatic liver damage; chronic alcoholism; cardiovascular diseases in the anamnesis; severe renal insufficiency; oppression of bone marrow hematopoiesis (incl.on the background of concomitant radiation or chemotherapy); acute infectious diseases of a viral, fungal or bacterial nature (including chicken pox, shingles); concurrent radiation therapy.

Dosing and Administration:

Intravenously drip, for 30 minutes.

Cancer of the pancreas, incl. local and metastatic monotherapy: 1000 mg / m² Once a week for 7 weeks followed by a weekly break. Then the drug is administered on the 1 st, 8 th and 15 th days of each 28-day cycle.

Non-small cell lung cancer, incl. local and metastatic

monotherapy: 1000 mg / m² in the 1st, 8th and 15th days of each 28-day cycle.
AT composition of combination therapy: 1250 mg / m² on the 1 st and 8 th day of each 21-day cycle or 1000 mg / m² in the 1st, 8th and 15th days of each 28-day cycle. Cisplatinum administered at a dose of 70 mg / m² in the 1st day of the cycle after the infusion of gemcitabine against a background of hyperhydration.

Breast cancer, incl. local and metastatic

monotherapy with the progression of the disease after first-line therapy, including anthracyclines: 1000-1200 mg / m² in the 1st, 8th and 15th days of each 28-day cycle.

AT composition of combination therapy as first-line therapy for the progression of the disease after neoadjuvant and / or adjuvant therapy involving anthracyclines: 1250 mg / m² in the 1 st and 8 th days in combination with paclitaxel, which is administered to gemcitabine at a dose of 175 mg / m² on the 1st day of each 21-day I / IV drip for 3 hours.

Urothelial cancer (urinary bladder (locally advanced, metastatic and superficial ;, ureter, urethra)

monotherapy: 1250 mg / m² in the 1st, 8th and 15th days of each 28-day cycle.

AT composition of combination therapy: 1000 mg / m² in the 1st, 8th and 15th 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.

Cancer of the ovary, incl. local and metastatic

monotherapy: 800-1250 mg / m² in the 1st, 8th and 15th days of each 28-day cycle.

In the composition combination therapy: 1000 mg / m² in the 1 st and 8 th days in combination with carboplatin in a dose AUC (area under the pharmacokinetic curve) of 4.0 mg / ml / min, which is injected immediately after the infusion of gemcitabine on the 1st day of each 21-day cycle.

Cervical cancer, incl. local and metastatic

AT composition of combination therapy: with locally advanced cancer consistent chemoradiotherapy (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.

Cisplatin is administered after gemcitabine at a dose of 70 mg / m² in the first day of the cycle against a background of hyperhydration.

With locally advanced cancer, simultaneous chemoradiotherapy gemcitabine is administered once a week, 1-2 hours before the start of radiotherapy, 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.

Common recommendations for all indications

The following scheme of administration is possible: 1000 mg / m² surface of the body. Infusions are carried out once a week for 3 weeks, after which they take a break for 1 week and repeat the course.

With the development of severe non-hematological toxicity (degree 3-4), with the exception of nausea, vomiting and alopecia, the dose of gemcitabine can be reduced to 50% of the recommended dose by the decision of the attending physician.

Correction of the dosing regimen in case of development of hematological toxicity

Before each introduction of gemcitabine, it is necessary to control the number of platelets, white blood cells and granulocytes. At signs of oppression of bone marrow function, it is necessary to suspend treatment or adjust the dose in accordance with the diagrams below.

When monotherapy or combined with cisplatin therapy for bladder cancer (urothelial cancer), non-small cell lung cancer, pancreatic cancer:

The total number of granulocytes (x10⁶/ l)		Platelets (x10⁶/ l)	% of recommended dose
≥ 1000	and	≥ 100,000	100
500-999	or	50,000-99,999	75
<500	or	< 50,000	Break

When combined with paclitaxel therapy for breast cancer

The total number of granulocytes (x10⁶/ l)		Platelets (x10⁶/ l)	% of the recommended dose
≥ 1200	and	≥75,000	100
1000-1199	or	50,000-75,000	75
700-999	and	≥ 50,000	50
<700	or	< 50,000	Break

When combined with carboplatin therapy for ovarian cancer.

The total number of oocyte granules (x10⁶/ l)		Platelets (x10⁶/ l)	% of the recommended dose
≥1500	and	≥ 100,000	100
1000-1499	and / or	75,000-99,999	50
<1000	and / or	< 75,000	Break

Special patient groups

Elderly patients (over 65 years of age)

Gemcitabine is well tolerated by patients of the older age group. Despite the age-related changes in the half-life and clearance of gemcitabine, there is no evidence that requires a change in the dosage regimen of the drug in this group of patients.

Patients with impaired hepatic and renal function

The experience of using gemcitabine in patients with impaired liver and kidney function is limited, and therefore it is recommended to use with caution.

Moderate or moderate severity of renal failure (glomerular filtration rate from 30 to 80 ml / min) has no significant effect on the pharmacokinetics of gemcitabine.

Children

The use of gemcitabine in children has not been studied.

Rules for preparing an infusion solution:

solvent - only 0.9% solution of sodium chloride for injections is used without preservatives.

To dissolve 200 mg of gemcitabine, at least 5 ml of solvent are added to the vial, to dissolve 1 g - at least 25 ml of the solvent and gently shake until completely dissolved. The resulting solution should be clear.

The maximum concentration of gemcitabine should not exceed 40 mg / ml. A prepared solution containing the desired dose of the preparation is diluted with a sufficient amount of solvent before administration for a 30-minute intravenous infusion. Before the introduction, it should be ensured that there are no suspended particles in the solution.

Side effects:

Estimated frequency of adverse reactions recommended by WHO: very often more than 10%; often - more than 1 and less than 10%; not often - more than 0.1 and less than 1%>; rarely - more than 0.01 and less than 0.1%; very rarely - less than 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 hepatic transaminases, alkaline phosphatase; often - anorexia, diarrhea, constipation, stomatitis, increased bilirubin level.

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

From the skin: often - a rash, itching, alopecia.

From the respiratory system: very often - shortness of breath; often - cough, rhinitis; not often - bronchospasm, interstitial pneumonia, pulmonary edema; rarely acute respiratory distress syndrome.

From the cardiovascular system: rarely - lowering blood pressure, chest pain, myocardial infarction, heart failure, arrhythmia.

From the central nervous system: often - headache, drowsiness, insomnia.

Other: very often - flu-like syndrome, peripheral edema; often-fever, chills, asthenia, back pain, myalgia; not often - paresthesia, violation of tendon reflexes, swelling of the face, the formation of extravasate (irritation, pain or redness) at the injection site, very rarely - anaphylactic reactions.

Overdose:

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

Treatment symptomatic. If you suspect an overdose, the patient should be under constant medical supervision, including the calculation of the blood formula.

The antidote is unknown.

Interaction:

When gemcitabine is combined with cisplatin, gastrointestinal toxicity (nausea and vomiting, diarrhea, stomatitis), hematologic toxicity, alopecia are more common.

The combination of gemcitabine with paclitaxel leads to an increase in hematological toxicity, usually controlled.

Gemcitabine has a radiosensitizing effect, therefore, when using this drug against radiation therapy, it is possible to expect intensification of radiation reactions. In the case of sequential chemo- and radiotherapy gemcitabine you can start to enter after resolving acute radiation reactions or at least one week after the end of radiation therapy. In turn, concomitant radiotherapy causes additive suppression of bone marrow function.

Drugs with immunosuppressive activity (azathioprine, chlorambucil, glucocorticosteroids, cyclophosphamide, ciclosporin, mercaptopurine) increase the risk of infection.

With the introduction of live viral vaccines, it is possible to intensify the replication of the vaccine virus and to increase the side effects, with the introduction of inactivated vaccines, the suppression of the production of antiviral antibodies (the interval between gemcitabine and vaccines is 3 to 12 months).

Studies of the compatibility of gemcitabine were not conducted.

It is inadmissible to mix gemcitabine with other medications.

Special instructions:

The use of gemcitabine should be carried out by specially trained medical personnel in accordance with established precautions when preparing, diluting injection solutions (in a sterile box using disposable surgical gloves and masks) and destroying needles, syringes, vials, ampoules and the remainder of the unused preparation.

Treatment with gemcitabine can begin with an absolute amount of granulocytes not less than 1500 / μl, platelets - not less than 100,000 / μl.

The decision to delay the next administration of the drug should be based on a clinical assessment by the doctor of the toxicity dynamics.

To detect nonhematological toxicity, a regular examination of the patient and evaluation 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.

In case of accidental ingestion of gemcitabine on the skin and mucous membranes, the affected area should be washed immediately with soap and water or thoroughly with a strong stream of water.

In patients with lung cancer or with lung metastases, the risk of side effects from the respiratory system is increased.

In case of confirmation or suspicion of pneumonitis caused by gemcitabine, treatment should be discontinued immediately.

If the first signs of hemolytic-uremic syndrome occur, treatment with gemcitabine should be stopped immediately.

When gemcitabine is used more than once a week or if an infusion is performed for more than 60 minutes, the frequency and severity of the adverse effects associated with gemcitabine therapy may increase.

Previous treatment with cytostatics increases the frequency and severity of leukopenia and thrombocytopenia (a progressive decrease in the number of leukocytes and platelets can occur after the completion of therapy).

The introduction of gemcitabine with metastases in the liver, with hepatitis and alcoholism in history, as well as with cirrhosis may develop liver failure.

The appearance of signs of bone marrow suppression, unusual bleeding or hemorrhages, black tarry stools, blood in the urine or feces, or pinpoint red spots on the skin require immediate medical attention.

They are used with caution in elderly people (increased risk of toxic effects on blood), in patients who have previously received cytotoxic drugs or radiation therapy.

Women and men during treatment with gemcitabine and at least 6 months after therapy should use reliable methods of contraception.

Dental interventions must be completed before the start of therapy or postponed until the blood picture is normalized. During treatment, use caution when using toothbrushes, threads or toothpicks.

During the period of treatment, vaccination with viral vaccines is not recommended.

Effect on the ability to drive transp. cf. and fur:During the period of application of the drug, patients are advised to carefully manage the car and engage in other potentially hazardous activities due to possible drowsiness. If this undesirable phenomenon develops, you should refrain from potentially dangerous activities.

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

Packaging:

200 mg or 1000 mg of active substance in a vial of clear, colorless glass, sealed with a bromobutyl stopper and crimped with an aluminum cap with a seal.

1 bottle with instructions for use in a pack of cardboard.

Storage conditions:

In a dry, protected from light place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

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

Terms of leave from pharmacies:On prescription

Registration number:LP-000815

Date of registration:06.10.2011 / 09.12.2014

Expiration Date:06.10.2016

The owner of the registration certificate:Heterose Labs LimitedHeterose Labs Limited India

Manufacturer: & nbsp

HETERO LABS, Limited India

Representation: & nbspHeterose Labs LimitedHeterose Labs LimitedIndia

Information update date: & nbsp21.03.2017

Illustrated instructions

Instructions

Gemcitabine (Gemcitabine)