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

Active substance:
Gemcitabine hydrochloride	227.7 mg	1138.5 mg	1707.8 mg
(corresponding to gemcitabine)	200 mg	1000 mg	1500 mg
Excipients:
Mannitol	200 mg	1000 mg	1500 mg
Sodium acetate trihydrate	20.73 mg	103.5 mg	155.5 mg
Sodium hydroxide	q.s. (forthe pH to 2.7-33)
Acid hydrochloric	q.s. (forthe pH to 2.7-33)

Description:White or almost white lyophilized mass or powder.

Pharmacotherapeutic group:antitumour agent, antimetabolite

ATX: & nbsp

L.01.B.C.05 Gemcitabine

Pharmacodynamics:

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 Gl / S. Meis 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). Trisphosphate 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 death (apoptosis).

Gemcitabine is also a strong radiosensitizer even at 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 (dFdCMP, dFdCDP and dFdCTP), of which active are considered dFdCDP and dFdCTP.

Gemcitabine is quickly excreted from the body with urine mainly as an inactive metabolite of 2'-deoxy-2 ', 2'-difluoruridine. Less than 10% of the intravenous dose is detected in the urine in the form of unchanged gemcitabine Systemic clearance, which ranges from about 30 l / h / m² up to 90 l / h / m², depends on age and sex: the rate of excretion in women is approximately 25% lower than that of men; Both in men and in women, the rate of excretion decreases with age.

The half-life period ranges from 42 minutes to 94 minutes.When the recommended dosing regimen is followed, the complete excretion of gemcitabine occurs within 5-11 h from the beginning of the 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 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 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.

Contraindications:

-increased sensitivity to the active substance or to any of the auxiliary substances,

-Birth and the period of breastfeeding,

-Children under 18 years of age (lack of sufficient data on efficiency and safety).

Carefully:

if there is 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 in anamnesis, with metastatic liver damage, hepatitis, alcoholism, concomitant radiotherapy, acute infectious diseases of the 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 / m²on 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 in the 1.8 and 15 days of each 28-day cycle. Cisplatinum is administered in a dose of 70-100 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 first-line therapy for the progression of the disease 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 in a dose of 175 mg / m², which is administered on the 1st day of each 21-day cycle intravenously drip for about 3 hours, before the administration of gemcitabine.

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 / m²in 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 1 st, 8 th and 15 th day 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 at a dose of 70 mg / m²after administration of gemcitabine in the first day of the cycle against a background of hyperhydration.

Correction of 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

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 in thecycle.

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	Canceling 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:

decrease in the absolute number of neutrophils <500 / μL, lasting more than 5 days,

a decrease in the absolute number of neutrophils <100 / μL, lasting more than 3 days,

febrile neutropenia,

a decrease in the number of platelets <25,000 / μl,

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

Correction of the dose of the drug in connection with the phenomena of nonhematological toxicity

To detect nonhematological toxicity, periodic physical examination and monitoring of liver and kidney functions should be performed. The dose of the drug can be reduced in each subsequent cycle or during the already started cycle, depending on the degree of manifestation of toxicity of the drugs prescribed to the patient. In the case of severe (grade 3 or 4) non-hematologic toxicity, with the exception of nausea / vomiting, gemcitabine therapy should be suspended or reduced in dosage, depending on the decision of the treating physician. The decision to resume treatment is taken by a doctor.

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, 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 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 of the drug in the bottle, slowly add the necessary amount of 0.9% solution of sodium chloride for injection (no less than the amount indicated in the table below) and gently shake the bottle until the content is completely dissolved.

Dosage of the drug in the vial	Required volume of 0.9% solution of sodium chloride for injection	Volume of reconstituted solution	Concentration of gemcitabine in solution
200 mg	5 ml	5.26 ml	38 mg / ml
1000 mg	25 ml	26.3 ml	38 mg / ml
1500 mg	37.5 ml	39.5 ml	38 mg / ml

The resulting solution should be clear.

The maximum concentration of the reconstituted solution of gemcitabine should not exceed 38 mg / ml, since at higher concentrations, an incomplete dissolution of the preparation 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 for a 30-minute intravenous infusion before administration.

Before parenteral administration of the drug solution, one should be convinced of the absence of undissolved particles in it and the color change of the solution.

The prepared drug solution is intended for single use only.

All unused product must be disposed of.

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 (aspartate aminotransferase, alanine aminotransferase), alkaline phosphatase; often - anorexia, diarrhea, constipation, stomatitis, increased bilirubin concentration; rarely - increased activity of gamma-glutamyltransferase; frequency can not be estimated on the basis of available data - ischemic colitis, toxic liver damage, including hepatic insufficiency with a lethal outcome.

From the urinary system: very often - hematuria and mild proteinuria; frequency can not be assessed on the basis of available data - acute 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 and skin appendages: very often - skin rashes, accompanied by itching, alopecia; often - itchy skin,increased sweating; rarely - ulceration, blistering, very rarely - severe skin reactions, including desquamation and bullous eruptions; the frequency can not be estimated - Lyell's syndrome, Stevens-Johnson syndrome.

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

From the cardiovascular system: rarely - lowering blood pressure, myocardial infarction, the frequency can not be assessed - arrhythmia (mainly supraventricular), heart failure, clinical signs of peripheral vasculitis and gangrene.

From the nervous system: often - headache, increased drowsiness, insomnia; the frequency can not be assessed - a stroke.

Other: very often - a feeling of malaise, flu-like syndrome, peripheral edema; often - fever, chills, asthenia, back pain, myalgia; rarely - swelling of the face, reactions at the injection site; very rarely - anaphylactic reactions.

Overdose:

Symptoms: myelodepression, paresthesia, severe skin rash.

With the introduction of gemcitabine in doses up to 5700 mg / m² intravenously drip for 30 minutes every 2 weeks there was no evidence of an overdose.

The antidote for gemcitabine is unknown.

If suspected overdose of gemcitabine should be monitored the degree of cytopenia and, if necessary, prescribe symptomatic therapy.

Interaction:

Specific studies of gemcitabine interactions have not been conducted.

Radiation therapy

Accompanying radiotherapy (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 tissue being irradiated 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 irradiation 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 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. So, in one of the studies II phase, 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): 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).

Immunodepressants (azathioprine, chlorambucil, glucocorticosteroids, cyclophosphamide, ciclosporin, mercaptopurine) increase the risk of infection.

Other types of interaction

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, featureMr.about in patients with reduced immune status, the interval between gemcitabine and such vaccines should be at least 3 months or more (up to 12 months), depending on the patient's immune status.

Incompatibility

Studies of the compatibility of gemcitabine were not conducted.

Do not mix gemcitabine with other medications.

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 should be stopped treatment and appropriate therapy.

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.

When treating patients who are on a controlled sodium diet should take into account the content in the preparation of sodium in the following amounts:

the 200 mg Gemcitabine honey pack contains 3.5 mg (<1 mmol) of sodium,

the 1000 mg Gemcitabine honey pack contains 17.5 mg (<1 mmol) of sodium,

the 1500 mg Gemcitabine honey pack contains 26.3 mg (<1 mmol) of sodium.

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 perform such actions. During the period of gemcitabine treatment, care must be taken when driving vehicles and engaging in potentially dangerous activities that require a high concentration of attention and speed of psychomotor reactions.

Form release / dosage:

Lyophilizate for solution for infusion.

Packaging:

200 mg, 1000 mg or 1500 mg of gemcitabine in a vial of colorless glass (type I, EF), sealed with a chlorobutyl rubber stopper and crimped with an aluminum cap with a polymer protective cap. A label is attached to the vial.

One vial with instructions for use in a cardboard pack.

Storage conditions:

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

Keep out of the reach of children!

Shelf life:3 years.

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

Terms of leave from pharmacies:On prescription

Registration number:LP-000150

Date of registration:12.01.2011

The owner of the registration certificate:medac GmbHmedac GmbH Germany

Manufacturer: & nbsp

medac, GmbH Germany

Representation: & nbspTIRUFARM, LLCTIRUFARM, LLCRussia

Information update date: & nbsp2015-12-24

Illustrated instructions

Instructions

Gemcitabine medak (Gemcitabine medac)