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

Gemcitabine is an antimetabolite of the group of pyrimidine analogues. The drug suppresses the synthesis of 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 with the formation of active diphosphate and triphosphate nucleosides. Diphosphate nucleosides inhibit ribonucleotide reductase, which is 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 lysis (apoptosis).

Gemcitabine is also a strong radiosensitizer even at concentrations lower than cytotoxic.

Pharmacokinetics:

Metabolized in cells of the liver, kidneys, blood under the action of the enzyme cytidine deaminase in stages, until the formation of an inactive metabolite of 2'-deoxy-2 ', 2'-difluoruridine. The volume of distribution depends to a great extent on the duration of the infusion and sex. Linkage to plasma proteins is low (less than 10%). System clearance, which ranges from about 30 l / h / m² up to 90 l / h / m², depends on age and sex (in women, the clearance is 25% less than in men, with age, the clearance of gemcitabine decreases). The half-life period ranges from 42 minutes to 94 minutes. It is mainly excreted by the kidneys in the form of an inactive metabolite of 2'-deoxy-2 \ 2'-difluoruridine (89%), and also unchanged (less than 10%); less than 1% - with calves.

With a reduced function of the kidneys in the body can accumulate inactive metabolite.

Indications:

- Non-small cell lung cancer

- Pancreas cancer

- Bladder Cancer

- Mammary cancer

- Locally or metastatic cervical cancer

Gemcitabine in monotherapy or in combination with other antitumor agents also shows activity in ovarian cancer, locally advanced small cell lung cancer, and locally advanced testicular cancers.

Contraindications:

-increased sensitivity to gemcitabine or other components of the drug

-Birth and lactation period

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), with concomitant radiotherapy, acute infectious diseases of viral, fungal or bacterial nature (including chicken pox, shingles).

Dosing and Administration:

Intravenously drip for 30 minutes.

Non-small cell lung cancer

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

Combination therapy with cisplatin: the recommended dose 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.

Cisplatin 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 is 1000 mg / m² or 1200 mg / m² on the 1 st and 8 th day of each 21-day cycle. Carboplatin is administered in 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 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 I / O cycle, drip for about 3 hours.

Urothelial cancer

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

Combination therapy: the recommended dose 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.

Ovarian Cancer

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

Combination therapy: the recommended dose is 1000 mg / m² on days 1 and 8, in combination with carboplatin at a dose of AUC of 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 is 1000 mg / m² 1 time per week for 7 weeks followed by a one-week break. Then the drug Gemcitabine-Teva is introduced on the 1st, 8th and 15th days of each 28-day cycle.

In case of development of hematological toxicity during the treatment cycle, the dose of Gemcitabine-Teva 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

ASC (absolute number of neutrophils) (in 1 μl)		The number of platelets (in 1 μl)	% from the standard dose
more than 1000	and	more	100
		100000
500 - 1000	or	50000 -	75
		100000
less than 500	or	less	defer
		50000	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

ACHN (in 1 μl)		The number of platelets (in 1 μl)	% from the standard dose
not less than 1200	and	more than 75,000	100
1000- less 1200	or	50000 - 75000	75
700 - less than 1000	and	not less than 50000	50
less than 700	or	less than 50000	defer 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 AFN is restored to at least 1500 / μL and the platelet count to 100,000 / μL.

Modification of the dose of gemcitabine, used in combination with carboplatin in the treatment of ovarian cancer

ACHN (in 1 μl)		The number of platelets (in 1 μl)	% from the standard dose
more 1500	and	not less than 100,000	100
1000- 1500	or	75000- 100000	50
less 1000	or	less than 75,000	defer 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 ACN reaches at least 1500 / μL and the platelet count 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:

a decrease in ACH of less than 500 / μL, lasting more than 5 days,
a decrease in ACH of less than 100 / μL, lasting more than 3 days,
febrile neutropenia,
a decrease in the number of platelets less than 25,000 / μl,
The cycle was delayed more than 1 week due to hematologic toxicity. Method of administration

Infusion introduction of the drug Gemcitabine-Teva is usually well tolerated by patients and can be performed in outpatient settings.In the case of extravasation, the infusion is discontinued and the Gemcitabine-Teva is injected into another vein. After the administration of Gemcitabine-Teva, the patient should be observed for some time.

Patients with impaired hepatic and renal function: use Gemcitabine-Teva in patients with liver failure or with impaired renal function should be taken with caution, as there is insufficient data on the use of gemcitabine in this category of patients. Renal failure of moderate or moderate severity (glomerular phylum ratethe process from 30 ml / min to 80 ml / min) has no significant effect on the pharmacokinetics of gemcitabine.

Elderly patients over 65 years of age: gem-citabine is well tolerated by patients older than 65 years. Specific recommendations for changing the dose of Gemcitabine-Teva for this population are absent.

Preparation of a solution for infusions

As a solvent, only 0.9% sodium chloride solution is used without preservatives.

To prepare a solution for infusion, the required quantity of 0.9% solution of sodium chloride for injections (not less than the amount indicated in the table below) is slowly introduced into the bottle and the vial is gently shaken until the content is completely dissolved.

Dosage of gemcitabine in vial (mg)	The required volume of 0.9% solution of sodium chloride for injection (ml)	Volume of reconstituted solution (ml)	Concentration of gemcitabine in solution (mg / ml)
200	5	5,26	38
1000	25	26,3	38

The resulting solution should be clear.

The maximum concentration of the reconstituted solution of gemcitabine ne should exceed 38 mg / ml, since at higher concentrations, an incomplete dissolution of the lyophilizate is possible.

The prepared solution containing the desired dose of gemcitabine is diluted with 0.9% sodium chloride solution for injection in an amount sufficient for a 30-minute IV infusion before administration.

Before parenteral administration of the solution of the drug Gemcitabine-Teva, one should be convinced of the absence of undissolved particles in it and the color change of the solution. The prepared solution of the drug Gemcitabine-Teva is intended for single use only.

Unused solution of Gemcitabine-Teva should be disposed of.

Side effects:

Adverse reactions are classified according to the recommendations of the World Health Organization: very often - not less than 10%; often - not less than 1%, but less than 10%; infrequently - not less than 0,1%, but less than 1%; rarely - not less than 0.01%, but less than 0.1%; very rarely (including isolated cases) - less than 0.01%.

From the hematopoiesis: very often - leukopenia, neutropenia, thrombocytopenia, anemia; often - febrile neutropenia; very rarely - thrombocytosis, microangiopathic hemolytic anemia (rapid reduction of hemoglobin with concomitant thrombocytopenia, increasedserum bilirubin, creatinine, urea nitrogen or increased lactate dehydrogenase (LDH) activity).

On the part of the digestive system: very often - nausea, vomiting, increased activity of "liver" transaminases, alkaline phosphatase; often - anorexia, diarrhea, constipation, stomatitis, ulceration of the oral mucosa, increased bilirubin concentration; rarely - increased activity of gamma-glutamintransferase; frequency can not be estimated on the basis of available data - toxic liver damage, including liver failure, ischemic colitis.

From the urinary system: very often - hematuria and mild proteinuria; the frequency can not be estimated on the basis of available data - acute renal failure, hemolyticuremic syndrome (microangiopathic hemolytic anemia, thrombocytopenia and acute renal failure).

From the skin and skin appendages: very often - alopecia; rarely - peeling, blistering and ulceration, increased sweating; very rarely - severe desquamation of the skin, bullous skin rash.

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 (BP), myocardial infarction; frequency can not be estimated on the basis of available data - heart failure, arrhythmia (mainly supraventricular).

From the nervous system: often - headache, drowsiness, insomnia, paresthesia; rarely - a violation of cerebral circulation, including stroke.

Allergic reactions: very often - a skin rash, accompanied by itching; very rarely anaphylactic reactions; frequency can not be estimated on the basis of available data - Lyell's syndrome, Stevens-Johnson syndrome.

From the musculoskeletal system: often - back pain, myalgia.

Other: very often - a feeling of malaise, flu-like syndrome,peripheral edema (usually after the cessation of treatment); often - fever, chills, asthenia; infrequent - swelling of the face; rarely - reaction at the injection site; very rarely peripheral vasculitis, gangrene.

Overdose:

Symptoms: myelosuppression, paresthesia, severe skin rash.

Treatment: there is no specific antidote. If you suspect an overdose, the patient should be under constant medical supervision, including the calculation of the blood formula; if necessary, symptomatic treatment.

Interaction:

Gemcitabine Teva has a radiosensitizing effect, so when using the drug on the background of radiotherapy, one can expect an increase in radiation reactions.

Reduces the production of antibodies and enhances side effects while using inactivated or live viral vaccines (the interval between the use of drugs should be from 3 to 12 months).

Special instructions:

Treatment with Gemcitabine Teva can be done only under the supervision of a doctor who has experience in the use of antitumor chemotherapy.

Before each administration of the drug, it is necessary to control the number of platelets,leukocytes and neutrophils in the blood. At signs of oppression of bone marrow function, it is necessary to suspend treatment or adjust the dose. Periodically, it is necessary to assess the function of the kidneys and liver.

Increasing the duration of infusion and the frequency of infusion leads to an increase in toxicity.

Introduction Gemcitabine Teva with metastases in the liver, with hepatitis and alcoholism in the history, as well as with cirrhosis increases the risk of developing liver failure.

When the first signs of hemolytic-uremic syndrome occur, treatment with Gemcitabine Teva should be discontinued.

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

When the first signs of pneumonitis or the appearance of infiltrates in the lungs, treatment with Gemcitabine Teva should be discontinued.

Gemcitabine Teva can be started to be administered after the resolution of acute radiation reactions or ns earlier than 7 days after the end of radiation therapy.

Women and men should be treated with Gemcitabine Teva and, at least 6 months after, should use reliable contraceptive methods.

Effect on the ability to drive transp. cf. and fur:During the treatment period, care should be taken when driving vehicles and engaging in 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 or 1 g.

Packaging:In bottles of colorless glass, ukuporennyh brombutilovoy stopper and obkatannye aluminum caps like "flip-off" with polypropylene cover gray. 1 bottle with instructions for use in a cardboard pack.

Storage conditions:

List B.

Lyophilizate - at a temperature of no higher than 30 ° C.

The prepared solution is at a temperature of no higher than 25 ° C.

Keep out of the reach of children!

Shelf life:

2 years.

The prepared solution is 6 hours.

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

Terms of leave from pharmacies:On prescription

Registration number:LSR-010215/08

Date of registration:15.12.2008 / 11.12.2012

Expiration Date:Unlimited

The owner of the registration certificate:Teva Pharmaceutical Enterprises Co., Ltd.Teva Pharmaceutical Enterprises Co., Ltd. Israel

Manufacturer: & nbsp

TEVA Pharmaceutical Works Private, Ltd. Co. Hungary

Representation: & nbspTeva Teva Israel

Information update date: & nbsp22.03.2017

Illustrated instructions

Instructions

Gemcitabine-Teva (Gemcitabine-Teva)