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

Excipients: Mannitol - 200 mg / 1000 mg, sodium acetate - 12.5 mg / 62.5 mg, hydrochloric acid - q.s. to a pH of 2.70-3.30 and sodium hydroxide is q.s. to a pH of 2.70 to 3.30.

Description:The lyophilized compact mass or powder is white or almost white in color.

Pharmacotherapeutic group:Antitumor agent - antimetabolites

ATX: & nbsp

L.01.B.C.05 Gemcitabine

Pharmacodynamics:Antitumor agent, antimetabolite of the group of pyrimidine analogs, suppresses the synthesis of deoxyribonucleic acid (DNA). It exhibits cyclospecificity by acting on cells in the S and G1 / S phases. 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).In pancreatic cancer, it is considered the drug of the first line: monotherapy causes clinical improvement in 25-40% of patients, and in 10-15% of patients - partial remission of 11-12 weeks; 23% of patients live more than a year. 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:

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, of which active are considered gemcitabine di and triphosphates. Gemcitabine is quickly excreted from the body by the kidneys mainly as an inactive metabolite of 2'-deoxy-2 ', 2'-difluoruridine.Less than 10% of the administered intravenous dose is found in the urine in the form of unchanged gemcitabine. 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. If the recommended dosage regimen is followed, the complete excretion of gemcitabine occurs within 5-11 hours from the start 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 advanced or metastatic non-small cell lung cancer as first-line therapy in combination with cisplatin, as well as in monotherapy in elderly patients with a functional status of 2 (ECOG-B03 scale);

- Inoperable, local-recurring or metastatic breast cancer after neoadjuvant and / or adjuvant therapy with anthracyclines included in the absence of contraindications to their use as part of combination therapy with paclitaxel;

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

- Locally spread or metastatic 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 spread or metastatic pancreatic cancer;

- Locally advanced or metastatic cervical cancer.

Contraindications:

- Hypersensitivity to gemcitabine or other component of the drug;

- pregnancy and the period of breastfeeding;

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

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

Pregnancy and lactation:Pregnancy and the period of breastfeeding are contraindications.

Dosing and Administration:

Gemtaz is administered intravenously drip for 30 minutes.

Locally advanced 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 (on a scale EC0G-B03).

Monotherapy: the recommended dose of the drug is 1000 mg / m² in the 1st, 8th and 15th days of each 28-day cycle.

Combination therapy with cisplatin: the recommended dose of the drug is 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 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 / m²on the 1 st and 8 th day 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.

Inoperable, locally resurgent shea metastatic breast cancer after neoadjuvant and / or adjuvant therapy with the inclusion of anthracyclines in the absence of contraindications to their appointment as part of combination therapy with paclitaxel.

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 after the administration of gemcitabine on the 1st day of each 21-day cycle intravenously by drip for approximately 3 hours.

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

Monotherapy: the recommended dose of the drug is 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, 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.

Locally or metastatic 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.

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 1 st day of each 21-day cycle.

Locally or metastatic pancreatic 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 days of each 2 8-day cycle.

Locally or metastatic cervical cancer.

Combination therapy: With locally advanced cancer (neoadjuvant) and with metastatic cancer gemcitabine is administered at a dose of 1250 mg / m²in the 1st and 8th days of each 21-day cycle. Cisplatinum is administered at a dose of 70 mg / m² after the introduction of gemcitabine 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 g, 5 days a week to a total focal dose of 50.4 g.

Corrector of the dose of the drug in connection with the phenomena of hematological toxicity

Start of treatment cycle

Regardless of the indications, before each injection of the drug it is necessary to evaluate the pure 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 50,000 to 100,000	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> 75,000	100
1000-<1200	or 50000 - 75000	75
700-< 1000	and ≥ 50000	50
<700	or <50000	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 amount 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

Absolute number of neutrophils (in 1 caste)	The number of platelets (in 1 μl)	% of the standard dose
> 1500	and ≥100,000	100
1000 - <1500	or 75,000- 100,000	50
< 1000	or <75,000	Canceling 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

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;

decrease in 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.

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 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 is not recommended for 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 without preservatives is used.

To prepare a solution of the drug in the bottle, slowly add the necessary amount of 0.9 / o sodium chloride solution for injections (not 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 injections	Volume of reconstituted solution	Concentration of gemcitabine in solution
200 mg	5 ml	5.26 ml	40 mg / ml
1000 mg	25 ml	26.3 ml	40 mg / ml

The resulting solution should be clear.

The maximum concentration of the reconstituted solution of gemcitabine should not exceed 40 mg / ml, since at higher concentrations, an incomplete dissolution of the preparation is possible.

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 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 preparation solution is stable from a physical and chemical point of view within 24 hours, provided that it was stored at controlled room temperature (20 ° C to 25 ° C). From the microbiological point of view, the prepared solution should be used immediately. In case the prepared solution was not used immediately and its preparation was carried out in a controlled and validated aseptic conditions, the retention time is typically no more than 24 hours at room temperature (20 ° C to 25 ° C) Preparation of the drug solution is only for single use. 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.

From the gastrointestinal tract: very often - nausea, vomiting,increased activity of "liver" transaminases (AST, ALT), alkaline phosphatase; often - anorexia, diarrhea, constipation, stomatitis, increased bilirubin concentration; rarely - increased activity of gamma-glutamyltransferase.

From the urinary system: very often - hematuria and mild proteinuria; rarely - renal failure, and clinical signs and symptoms similar to uremic syndrome (reduced hemoglobin, increased creatinine concentration, urea and / or activity of serum lactate dehydrogenase).

From the skin and subcutaneous tissues: very often - skin rashes, accompanied by itching, alopecia; often - skin itching, increased sweating; rarely - skin 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 pneumonitis, 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-body temperature increase, chills, asthenia, back pain, myalgia; infrequent - swelling of the face; very rarely - 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 case of suspected overdose, the patient should be under constant medical supervision, including the calculation of the blood formula, if necessary, symptomatic treatment. The antidote is unknown.

Interaction:

Radiation therapy

Concomitant radiation therapy (concurrent 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,dose 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 irradiation on the chest region, significant toxicity was noted in the form of severe and potentially life-threatening inflammation of the mucous membranes, mainly esophagitis and pneumonitis, especially in patients with high 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 essential data,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).

Other drugs that cause oppression of bone marrow function, and radiation therapy potentiate the effect and addatively inhibit the function of the bone marrow. Azathioprine, chlorambucil, glucocorticoids, cyclophosphamide, ciclosporin, mercaptopurine and other immunosuppressive drugs 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.

Compatibility

Studies of the compatibility of the drug Gemtaz were not conducted.It is not recommended to mix Gemtaz with other medications.

Special instructions:

Treatment with Gemtaz can be done only under the supervision of a doctor who has experience in carrying out anti-tumor chemotherapy.

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). It is necessary to carry out regular monitoring of the picture of peripheral blood, the activity of "liver" transaminases and the content of creatinine in the blood serum. Increasing the duration of infusion and the frequency of administration leads to greater toxicity. When oppression of the bone marrow is necessary to suspend treatment or adjust the dose. Women of reproductive age and men need to use effective contraceptive measures. The prepared solution should be kept at room temperature (15 to 30 ° C) and used within 24 hours. Do not freeze it. crystallization may occur. The optimal regimen for the safe administration of gemcitabine in combination with therapeutic regimens of radiotherapy has not been determined to date.

Effect on the ability to drive transp. cf. and fur:During the treatment period, care must be taken when driving vehicles and engaging in other potentially hazardous activities requiring increased attention and speed of psychomotor reactions.

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

Packaging:

200 gm gemcitabine in a 10 ml transparent glass vial made of Type I glass, sealed with a gray bromobutyl stopper with aluminum rolling and a protective polypropylene cap (flip-off). 1 bottle with instructions for use in a cardboard box.

For 1000 mg of gemcitabine in a clear glass vial of 50 ml of type I glass, sealed with a gray-bromobutyl stopper with aluminum rolling and a protective polypropylene cap (flip-off). 1 bottle with instructions for use in a cardboard box.

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.

Terms of leave from pharmacies:On prescription

Registration number:LP-001201

Date of registration:11.11.2011

Expiration Date:11.11.2016

The owner of the registration certificate:San Pharmaceutical Industries Co., Ltd.San Pharmaceutical Industries Co., Ltd. India

Manufacturer: & nbsp

Sun Pharmaceutical Industries, Ltd. India

Representation: & nbspSAN PHARMACEUTICAL INDUSTRIES LTD. SAN PHARMACEUTICAL INDUSTRIES LTD. India

Information update date: & nbsp21.03.2017

Illustrated instructions

Instructions

Gemtaz (Gemtaz)