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

Excipients: mannitol 200/1000 mg; sodium acetate trihydrate 20.74 / 103.70 mg corresponding to sodium acetate, anhydrous 12.5 / 62.5 mg, sodium hydroxide (1 M solution) to pH 3.0 (2.8-3.2).

Description:The porous mass is from white to almost white.

Pharmacotherapeutic group:Antitumor 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 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 that catalyzes the formation, deoxynucleoside triphosphates required for DOC 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 radiosensitizer even in concentrations lower than cytotoxic.

Pharmacokinetics:

Pharmacokinetic data were evaluated when infusions were administered to patients for 0.4-1.2 hour doses from 500 to 2592 mg / m².

The maximum concentration in, blood plasma (measured within 5 minutes after the end of infusion) is from 3.2 to 45.5 μg / ml. After a single infusion of 30 minutes in a dose of 1 g / m² the concentration in the blood plasma of the starting substance is above 5 μg / ml for about 30 minutes after the end of the infusion and above 0.4 μg / ml for an additional hour thereafter.

Linkage to plasma proteins is low (less than 10%).

The volume of distribution to the central chamber for women is 12.4 l / m² and 17.5 l / m² for men (with interindividual variability of 91.9%). The volume of distribution to the peripheral chamber is 47.4 l / m². The volume of the peripheral compartment does not depend on the sex.

Metabolised in cells of the liver, kidneys, blood - and other tissues by the enzyme cytidine deaminase. With intracellular metabolism of gemcitabine, mono-, di-, and triphosphates are formed, the latter two being active metabolites. Data, intracellular metabolites, are not found in blood plasma and urine.The primary metabolite of 2'-deoxy-2 ', 2'-difluoruridine is non-active, it is found in plasma and urine. After a week, 92-98% of gemcitabine is metabolized after administration.

The half-life (T_1/2) depends on sex and age and is 42 - 94 minutes. When gemcitabine is administered at the recommended doses, the drug is withdrawn 5 to 11 hours after the start of the infusion.

The system clearance varies from 29.2 l / h / m² up to 92.2 l / h / m² and depends on age and sex (with interindividual variability 52.2%). In women, the clearance of the drug is slightly lower than that of men (approximately 25%). With age, the clearance values decrease for both men and women. With the introduction of gemcitabine in the form of an infusion of 30 minutes with a dose of 1 g / m2 with a decrease in clearance values, there is no need to reduce the dose of the drug in both men and women.

Kidney clearance is 2-7 l / h / m².

It is excreted mostly by the kidneys (99%) and less than 1% by the intestine. Less than 10% of the drug is excreted by the kidneys unchanged.

With the mode of administration once a week gemcitabine does not accumulate in the body.

Pharmacokinetics in special clinical cases

When combined therapy with paclitaxel, pharmacokinetics is not impaired in both components.

With combined therapy with carboplatin, the pharmacokinetics of gemcitabine is not impaired.

Impaired renal function

With renal insufficiency of mild and moderate severity (glomerular filtration level from 30 ml / min to 80 ml / min), there was no significant effect on 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 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 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.

Contraindications:Hypersensitivity, pregnancy, lactation, children under 18 years of age (efficacy and safety not studied).

Carefully:Hepatic failure, severe renal failure, oppression of bone marrow hematopoiesis (including on the background of concomitant radiation or chemotherapy), acute infectious diseases of viral, fungal or bacterial nature (including chicken pox, shingles).

Pregnancy and lactation:

There is insufficient data on the use of Gemcitabine-Aktavis during pregnancy. The use of the drug during pregnancy is contraindicated.

It is not known whether gemcitabine in breast milk. If Gemcitabine-Aktavis is used, breast-feeding should be discarded.

Dosing and Administration:

Gemcitabine-Aktavis is administered intravenously (IV) dropwise for 30 minutes.

With non-small cell lung cancer (locally advanced or metastatic) in the form of monotherapy, the recommended dose of the drug is 1000 mg / m² on days 1, 8 and 15 of each 28-day cycle.

When used in combination therapy with Iisplatinum, 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 administered in a dose of 70-100 mg / m² in the 1st day of the cycle after the infusion of gemcitabine against a background of hyperhydration.

When used in 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 pharmacokinetic curve "concentration-time") 5.0 mg / ml * min on the 1st day of the cycle after the infusion of gemcitabine.

With breast cancer (locally advanced or metastatic) in the form of monotherapy in the progression of the disease after first-line therapy, including anthracyclines in the absence of contraindications to them, the recommended dose of the drug is 1000-1200 mg / m² in the 1.8 and 15 days of each 28-day cycle.

When used as a first-line therapy in combination therapy as a disease progresses after neoadjuvant and / or adjuvant therapy involving anthracyclines, the recommended dose is 1250 mg / m² at 1 and 8 days in combination with paclitaxel, which is administered after gemcitabine at a dose of 175 mg / m² on the 1st day of each 21-day I / IV cycle for approximately 3 hours.

In urothelial cancer (topical, metastatic and superficial) in the form of monotherapy, the recommended dose of the drug is 1250 mg / m² on days 1, 8 and 15 of each 28-day cycle.

When used in combination therapy, the recommended dose of the drug is 1000 mg / m² at 1, 8 and 15 days in combination with cisplatin, which is administered in a dose of 70 mg / m² immediately after the infusion of gemcitabine on or on day 2 of each 28-day cycle.

In epithelial ovarian cancer (locally or metastatically) in the form of monotherapy, the recommended dose of the drug is 800-1250 mg / m², on-1, 8 and 15 days of each 28-day cycle.

When used in combination therapy, the recommended dose of the drug is 1000 mg / m² at 1 and 8 days in combination with carboplatin in a dose AUC 4.0 mg / ml * min, which is injected immediately after the infusion of gemcitabine on day 1 of each 21-day cycle.

With pancreatic cancer (locally advanced or metastatic) in the form of monotherapy, the recommended dose of the drug is 1000 mg / m² 1 time per week for 7 weeks followed by a one-week break.The preparation is then administered on days 1, 8 and 15 of each 28-day cycle.

With cervical cancer (locally advanced or metastatic) is combined therapy. With locally advanced cancer with sequential chemotherapy and radiation therapy (neoadjuvant) and with metastatic cancer gemcitabine administered at a dose of 1250 mg / m² on days 1 and 8 of each 21-day cycle. Cisplatin is administered after administration of gemcitabine at a dose of 70 mg / m² in the 1st day of the cycle against a background of hyperhydration.

With locally advanced cancer with simultaneous chemotherapy and radiotherapy gemcitabine administered once a week for 1-2 hours before the start of radiation therapy 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.

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 gemcitabine it is necessary to control the number of platelets, leukocytes and granulocytes in the blood. At signs of oppression of bone marrow function, it is necessary to suspend treatment or adjust the dose.

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.

In case of development of hematological toxicity, the dose of gemcitabine can be reduced, or the drug administration should be postponed in accordance with the following scheme.

Modification of the dose of gemcitabine used in monotherapy or in combination with cisplatin in the treatment of urothelial 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 previous dose
> 1000	and> 100 000	100
500-1000	or 50 000-100 000	75
<500	or <50 000	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 previous dose
≥1200	and	> 75 000	100
1000-<1200	or	50 000-75 000	75
700-<1000	and	≥50 000	50
<700	or	<50 000	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 number 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.

The absolute amount of neutrophils (in 1 μl)	The number of platelets (in 1 μl)	% of previous dose
> 1500	and ≥ 100,000	100
1000-1500	or 75 000-100 000	50
<1000	or <75,000	Postpone the introduction *

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 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,

- 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 cases of nausea / vomiting,therapy with gemcitabine should be suspended or reduced in dose depending on the decision of the attending physician. The decision to resume treatment is taken by a doctor.

The data proving that patients in the elderly need to adjust the dose is not available, although the clearance of gemcitabine and T_1/2 change with age.

Use gemcitabine In patients with hepatic impairment or with impaired renal function, caution should be exercised. There is no sufficient data on the use of the drug in this category of patients.

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

The use of gemcitabine in children has not been studied.

Rules for the preparation of a solution for infusions

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

The maximum concentration of gemcitabine should not exceed 40 mg / ml. In solutions prepared with a concentration of more than 40 mg / ml, an incomplete dissolution of the lyophilizate is possible.

1. To prepare the solution, you must adhere to the requirements for the preparation of solutions for intravenous administration.

2. For the preparation of the solution for infusion, the contents of the 200 mg bottle are dissolved in 5 ml, and 1 g in 25 ml of 0.9% sodium chloride solution for injection (without preservatives). The total volume after dilution is 5.26 ml (for 200 mg) and 26.3 ml (for 1000 mg), respectively. At this dilution, the concentration of gemcitabine is 38 mg / ml, taking into account the volume of lyophilizate. The vial should be shaken until the lyophilizate is completely dissolved. A prepared gemcitabine solution containing the desired dose of the preparation is diluted with 0.9% sodium chloride solution for injections (no preservatives) before administration, in an amount sufficient for a 30-minute IV infusion. The resulting solution should be transparent, from colorless to pale yellow.

3. Before parenteral administration, it is necessary to visually monitor the prepared solution for mechanical impurities and discoloration. Do not inject the solution if particles are found in it.

Side effects:

Adverse reactions occurring more often than in single cases are listed according to the following gradation: very often (> 10%); often (> 1%, <10%); infrequently (> 0.1%, <1%); rarely (> 0.01%, <0.1%); very rarely (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 "liver" transaminases, alkaline phosphatase; often - anorexia, diarrhea, constipation, stomatitis, increased bilirubin concentration; rarely - increased activity of alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase, alkaline phosphatase; the frequency is unknown - ischemic colitis, serious complications resulting from hepatotoxicity, including hepatic insufficiency, fatal.

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

From the skin and soft tissues: very often - a skin rash, usually accompanied by itching, alopecia; often - increased sweating, itching; rarely-ulceration,the formation of vesicles and wounds on the skin; very rarely - severe reactions from the skin, including desquamation of the epithelium and biliary rash; frequency unknown - Lyell syndrome, Stevens-Johnson syndrome.

From the respiratory system: very often - shortness of breath; often - cough, rhinitis; infrequently - bronchospasm, interstitial pneumonia, frequency unknown - pulmonary edema, acute respiratory distress syndrome adults.

From the cardiovascular system: rarely - lowering blood pressure, myocardial infarction; frequency unknown - stroke, heart failure, arrhythmia (usually supraventricular), clinical signs of peripheral vasculitis and gangrene.

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

Local reactions: rarely - reactions at the injection site, usually light in nature;

Other: very often - influenza-like syndrome (accompanied by the following symptoms: fever, headache, chills, myalgia, asthenia and anorexia, also reported on the development of cough, rhinitis, malaise, increased sweating and sleep disturbances), peripheral edema,including puffiness of the face (as a rule, puffiness occurs after stopping the drug); often - fever, chills, asthenia, back pain, myalgia; very rarely anaphylactoid reactions; frequency unknown - radiation toxicity.

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:

Concomitant radiation therapy causes an additive inhibition of bone marrow function (when gemcitabine is administered at a dose of 1 g / m² (up to 6 weeks of treatment) against the background of radiotherapy on the chest area in patients with non-small cell lung cancer,marked significant toxicity in the form of severe and potentially life-threatening esophagitis and pneumonia).

Immunosuppressants (azathioprine, chlorambucil, glucocorticosteroid agents, cyclophosphamide, ciclosporin, mercaptopurine) increase the risk of infection.

Reduces the production of antibodies and enhances side effects when using inactivated or live viral vaccines at the same time (the interval between medicinal products should be from 3 to 12 months).

Special instructions:

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

The drug is well tolerated when infusion is introduced and - can be administered on an outpatient basis.

If an extravasation occurs, stop the infusion and continue the injection through another vein. Care should be taken to monitor the patient's condition after administration.

Hematological toxicity

Gemcitabine is able to inhibit bone marrow function, which can manifest as leukopenia, thrombocytopenia and anemia.When oppression of the bone marrow is necessary to suspend treatment or adjust the dose.

Previous treatment with cytostatics increases the frequency and severity of leukopenia and thrombocytopenia (a progressive decrease in the number of white blood cells and thrombocytes can be observed after the completion of therapy).

In patients with oppression of bone marrow hematopoiesis, the drug should be used with caution.

Liver failure

The introduction of gemcitabine in metastases in the liver, with hepatitis, alcoholism in history and with cirrhosis increases the risk of developing liver failure.

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.

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

Other precautions

Women and men of childbearing age should be treated with gemcitabine and, at least 6 months after the therapy, reliable methods of contraception should be used. In case of pregnancy, the patient should immediately notify the attending physician.Man before treatment with gemcitabine-Actavis should deliver sperm for cryopreservation, since, after treatment of infertility may develop.

It is not recommended to administer live vaccines during the treatment with gemcitabine.

In view of the possibility of side effects from the circulatory system during treatment with gemcitabine should be, caution in patients with diseases of the cardiovascular system in history.

In the treatment of gemcitabine reported development of side effects of the respiratory system (lung edema, pneumonia or acute adult respiratory distress syndrome). The etiology of these phenomena is unknown. When the first signs of pneumonitis or the appearance of infiltrates in the lungs, treatment with gemcitabine should be discontinued.

In rare cases, the treatment of gemcitabine reported the development of symptoms of hemolytic-uremic syndrome. At the first sign of occurrence of microangiopathic hemolytic anemia, such as a sharp decrease in hemoglobin in thrombocytopenia, increasing the concentration of bilirubin, serum creatinine, urea, lactate dehydrogenase or nitrogen discontinue gemcitabine.Renal dysfunction may not occur if therapy is discontinued; in this case, hemodialysis may be required.

The prepared solution should be stored at room temperature not higher than 25 ° C and used within 24 hours, it should not be cooled and frozen. this can lead to crystallization.

When preparing the solution, the protective equipment necessary for working with cytostatic preparations (mask and gloves) should be used. If the product gets into the eyes during the preparation of the solution, this can cause severe irritation. In this case, rinse immediately with water. If irritation persists, consult a doctor. If the solution gets on the skin, it should be washed off with water. 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). Increasing the duration of infusion and the frequency of administration leads to greater toxicity. 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 that require increased concentration and speed of psychomotor reactions.

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

Packaging:

200 mg and 1000 mg of lyophilizate in colorless vials of borosilicate glass type I (Eur.Ph.) With a capacity of 10 ml and 50 ml or 57 ml respectively, sealed with bromobutyl type I cork of gray color (Eur.Ph.) with an aluminum cap polypropylene disc. Vials can be covered with a transparent protective layer of shrink film. 1 bottle per cardboard pack together with instructions for use.

Storage conditions:

At a temperature not higher than 25 ° C, do not refrigerate or freeze.

The prepared solution should be stored at a temperature of about 25 ° C not more than 24 hours, do not cool or freeze. 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-001436

Date of registration:17.01.2012 / 21.03.2013

Expiration Date:17.01.2017

The owner of the registration certificate:Actavis PTS ehf GroupActavis PTS ehf Group Iceland

Manufacturer: & nbsp

S.C. SINDAN-PHARMA S.R.L. Romania

ACTAVIS ITALY, S.p.A. Italy

Representation: & nbspAktavis, Open Company Aktavis, Open Company

Information update date: & nbsp21.03.2017

Illustrated instructions

Instructions

Gemcitabine-Aktavis (Gemcitabine Actavis)