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GEMCITABEL

Trade name: Gemcitabel.

International nonproprietary name: Gemcitabine.

Description: white or off-white powder in the form of a layer or individual aggregates or free-flowing powder.

Composition: each 10 ml vial contains active substance: gemcitabine (as gemcitabine hydrochloride) – 200 mg; excipients: mannitol, sodium acetate (as sodium acetate trihydrate).

Dosage form: lyophilized powder for solution for infusion.

Therapeutic category: Antineoplastic agents. Antimetabolites. Pyrimidine analogues.

ATC code: L01BC05.

Pharmacological properties

Pharmacodynamics

Cell culture cytotoxicity

Gemcitabine demonstrates apparent cytotoxicity against the range of cultured mouse and human cancer cells. Gemcitabine acts phase-specifically killing primarily the cells at the stage of DNA synthesis (S-phase) and under certain conditions blocks G1/S phase transition. Cytotoxicity of gemcitabine in vitro is concentration- and time-dependent.

Antineoplastic activity in preclinical models

Dependence of gemcitabine’s antineoplastic activity on frequency of administration was demonstrated in animal models of cancer. The drug’s daily administration caused high incidence of lethal cases among animals with low antineoplastic activity. However, when administered once in three or four days in doses below lethal, gemcitabine showed significant antineoplastic activity against a wide range of tumors in mice.

Mode of action

Intrinsic cellular metabolism and mode of action: gemcitabine (dFdC), being a pyridine antimetabolite, is metabolised in the cell by nucleoside kinase forming active di- (dFdCDP) and triphosphate (dFdCTP) nucleosides. The drug’s cytotoxicity is caused by DNA synthesis inhibition by two mechanisms: due to dFdCDP and dFdCTP. In the first case, dFdCDP inhibits the ribonucleotide reductase which is the only catalyst of deoxynucleoside triphosphates (dCTP) formation reactions necessary for DNA synthesis. This leads to overall lowering of deoxynucleosides and, particularly, of dCTP. In the second case, dFdCTP competes with dCTP for incorporation into DNA (self-potentiation).

Small amounts of gemcitabine can incorporate into RNA, as well. Thus, lowered intracellular dCTP concentration enhances dFdCTP incorporation into DNA. DNA polymerase epsilon cannot remove gemcitabine and repair the nascent DNA strands. Upon gemcitabine’s incorporation into DNA, another nucleotide attaches to the nascent chain which leads to complete inhibition of the subsequent DNA synthesis (quenched termination) and programmed cell death (apoptosis).

Clinical data

 

Bladder cancer

Clinical trial in patients with advanced or metastatic urothelial carcinoma showed absence of difference of gemcitabine/cisplatin line of therapy vs. methotrexate/vinblastine/ adriamycin/cisplatin therapy (MVAC) in duration of survival median (12.8 and 14.8 months, respectively; p = 0.547), time to disease progression (7.4 and 7.6 months, respectively; p = 0.842) and response rate (49.4% and 45.7 %, respectively; p = 0.512) were concerned. However, the toxicological profile of combination of gemcitabine and cisplatin was better than that of MVAC.

Pancreatic cancer

In the randomised clinical trial in patients with advanced or metastatic pancreatic cancer gemcitabine showed higher statistically significant response rate than 5-fluorouracil (23.8 % and 4.8 %, respectively; p = 0.0002). The increased time to disease progression from 0.9 to 2.3 months (log-rank p < 0.0002) and increased median survival from 4.4 to 5.7 months (log-rank p < 0.0024) in patients receiving gemcitabine therapy vs. those receiving 5-fluorouracil were statistically significant, as well.

Non-small cell lung cancer

In the randomised clinical trial in patients with localised or metastatic non-small cell lung cancer (NSCLC) gemcitabine in combination with cisplatin showed higher statistically significant response rate than cisplatin monotherapy (31.0 % and 12.0 %, respectively; p < 0.0001). The increased time to disease progression from 3.7 to 5.6 months (log-rank p < 0.0012) and increased median survival from 7.6 to 9.1 months (log-rank p < 0.004) in patients receiving therapy with gemcitabine/cisplatin combination vs. those receiving cisplatin monotherapy were statistically significant, as well.

In another randomised clinical trial in patients with stage IIIB or IV NSCLC gemcitabine in combination with cisplatin showed higher statistically significant response rate than combination of cisplatin with etoposide (40.6 % and 21.2 %, respectively; p = 0.025). Statistically significant increase of time to disease progression from 4.3 to 6.9 months (p = 0.014) in patients receiving gemcitabine/cisplatin combination vs. etoposide/cisplatin therapy was revealed.

In both trials the tolerability of the main and the control lines of therapy was comparable.

Ovarian cancer

In the randomised clinical trial patients with advanced epithelial ovarian cancer with relapse at least 6 months after the completion of the platinum-based therapy were randomised for treatment with gemcitabine and carboplatin (GCb) or carboplatin (Cb). Statistically significant increase of the time to disease progression from 5.8 to 8.6 months (log-rank p = 0.0038) was revealed in patients of the GCb group vs. those in the Cb group. The difference in the response rate amounted to 47.2 % in the GCb group vs. 30.9 % in the Cb group (p = 0.0016) and the median survival – to 18 months (GCb) vs. 17.3 (Cb) (p = 0.73).

Breast cancer

In the randomised clinical trial in patients with localised unresectable or metastatic breast cancer with relapse after adjuvant/non-adjuvant chemotherapy gemcitabine in combination with paclitaxel showed higher statistically significant increase of the time to recorded disease progression from 3.98 to 6.14 months (log-rank p = 0.0002) than paclitaxel monotherapy. The absolute survivability amounted to 18.6 vs. 15.8 months (log-rank p = 0.0489, HR 0.82) in patients of the gemcitabine/paclitaxel group vs. those in the paclitaxel group with absolute response rate of 41.1% and 26.2%, respectively (p = 0.0002).

Pharmacokinetics

Plasma concentration peak (within 5 minutes after the end of the infusion) amounts to 3.2 – 45.5 μg/ml. Plasma concentration of the original compound upon administration of 1000 mg/m2/30 minutes exceeds 5 μg/ml within 30 minutes after the end of the infusion and remains above 0.4 μg/ml within one hour.

Distribution

Gemcitabine distribution volume in the central compartment is above 12.4 l/m2 in women and 17.5 l/m2 in men (individual variability amounts to 91.1%). Distribution volume in the peripheral compartment amounts to 47.41 l/m2. Peripheral compartment volume is not sex-dependent. Gemcitabine is insignificantly bound with plasma proteins.

Elimination half-life varies from 42 to 94 minutes depending on age and sex. For the recommended dose the elimination half-period of gemcitabine should amount to 5 to 11 hours from the beginning of the infusion. Gemcitabine does not accumulate when administered once a week.

Metabolism

Gemcitabine is quickly metabolised by cytidine desaminase in liver, kidneys, blood, and other tissues. As a result of gemcitabine intrinsic cellular metabolism gemcitabine mono-, di-, and triphosphates are generated (dFdCMP, dFdCDP, and dFdCTP), of which dFdCDP and dFdCTP are considered active. These intrinsic cellular metabolites are not detected in plasma and urine. Primary metabolite 2’-deoxy-2’,2’-difluorouridine (dFdU) is not active and is detected in plasma and urine.

Excretion

Clearance from the system varies from 29.2 l/h/m2 to 92.2 l/h/m2 depending on sex and age (individual variability amounts to 52.2 %). Clearance in women is about 25% lower than that in men. With age, gemcitabine clearance is reduced in both men and women. With low clearance, both in men and women, no reduction of gemcitabine recommended dose 1000 mg/m2 during 30 minutes’ infusion is required.

Less than 10 % of the intravenously administered dose is detected in urine as unchanged drug. Renal clearance is between 2 to 7 l/h/m2.

During one week after administration of gemcitabine 92 % to 98 % of the drug dose is excreted: 99 % with urine (mainly as dFdU) and 1 % with faeces.

dFdCTP kinetics

This metabolite is detected in mononuclear cells of peripheral blood and the data below refer to the specified cells. Intracellular concentration increases in proportion to the administered dose of gemcitabine. Upon administration of 35 to 350 mg/m2/30 minutes, the steady-state concentration amounts to 0.4 – 5 μg/ml. When gemcitabine plasma concentration 5 μg/ml is exceeded, dFdCTP intracellular level stops increasing, indicating its saturating capacity in these cells. Half-elimination period amounts to 0.7 – 12 hours.

dFdU kinetics

Plasma peak concentration (3 – 5 minutes after the end of the 30 minutes’ infusion, 1000 mg/m2): 28 – 52 μg/ml. Minimum concentration after administration of the drug once a week: 0.07 – 1.12 μg/ml without apparent accumulation.

Three-phase curve of plasma concentration change in time, average half-elimination period in the final phase – 65 hours (the range of 33 – 84 hours).

dFdU formation from the original substance: 91 – 98 %.

Average distribution volume in the central compartment: 18 l/m2 (the range of 11 – 22 l/m2). Average distribution volume in the steady-state phase (Vss): 150 l/m2 (the range of 11 – 22 l/m2). Tissue distribution: broad. Average apparent clearance: 2.5 l/h/m2 (the range of 1 – 4 l/h/m2). All of the metabolite is eliminated with urine.

combined therapy with gemcitabine and paclitaxel

combined therapy does not affect pharmacokinetics of gemcitabine and paclitaxel.

combined therapy with gemcitabine and carboplatin

combined therapy with carboplatin does not affect pharmacokinetics of gemcitabine.

Renal failure

Light and average renal failure (GFR between 30 ml/min and 80 ml/min) does not have significant effect on gemcitabine pharmacokinetics.

Indications for use

-           treatment of localised or metastatic bladder cancer in combination with cisplatin.

-           treatment of localised or metastatic pancreatic adenocarcinoma.

-           first-line therapy of localised or metastatic non-small cell lung cancer (NSCLC) in combination with cisplatin. Gemcitabine monotherapy is possible in elderly patients or patients with physical function 2.

-           treatment of localised or metastatic epithelial ovarian cancer in combination with carboplatin in relapse patients after at least 6 months of delaying time to relapse after the end of the first line of platinum-based therapy.

-           complex treatment with paclitaxel of localised unresectable or metastatic breast cancer in relapse patients after adjuvant/non-adjuvant chemotherapy. The primary therapy shall include anthracycline in absence of contraindications.

Dosage and administration

Gemcitabine can be prescribed only by chemotherapist specialising in antineoplastic therapy.

Gemcitabine shall be administered by intravenous drip-feed for 30 minutes.

Bladder cancer

Combined therapy

The recommended dose is 1000 mg/m2 for 30 minutes. The drug is administered on day 1, 8 and 15 of each 28 days’ cycle in combination with cisplatin. The recommended dose of cisplatin is 70 mg/m2 on day 1 or 2 after gemcitabine of each 28 day’s cycle. Then this 4 weeks’ cycle is repeated. Dose reduction with each subsequent cycle or during the cycle is possible on the basis of the toxicity level of the drug in patient.

Pancreatic cancer

The recommended dose is 1000 mg/m2 for 30 minutes. The drug is administered once a week for 7 weeks, with a subsequent one weeks’ break. The subsequent cycles shall consist of 4 weeks where the drug shall be administered once a week for the first 3 weeks in a row. Dose reduction with each subsequent cycle or during the cycle is possible on the basis of the toxicity level of the drug in patient.

Non-small cell lung cancer

Monotherapy

The recommended dose is 1000 mg/m2 for 30 minutes. The drug is administered once a week for 3 weeks, with a subsequent one weeks’ break. This 4 weeks’ cycle is then repeated. Dose reduction with each subsequent cycle or during the cycle is possible on the basis of the toxicity level of the drug in patient.

Combined therapy

The recommended dose is 1250 mg/m2 for 30 minutes. The drug is administered on day 1 and 8 of the 21 days’ cycle. Dose reduction with each subsequent cycle or during the cycle is possible on the basis of the toxicity level of the drug in patient. The cisplatin dose is 75 – 100 mg/m2 once in 3 weeks.

Breast cancer

Combined therapy

The recommended drug dose – 1250 mg/m2 on day 1 and 8 (21 days’ cycle) in combination with paclitaxel which is administered before gemcitabine in the dose of 175 mg/m2 on day 1 of each 21 days’ cycle by intravenous drip-feed for about 3 hours. Dose reduction with each subsequent cycle or during the cycle is possible on the basis of the toxicity level of the drug in patient. The absolute granulocyte count in patient before the initiation of gemcitabine/paclitaxel therapy shall amount to at least 1500x106/l.

Ovarian cancer

Combined therapy

The recommended drug dose – 1000 mg/m2 on days 1 and 8 (21 days’ cycle) in combination with carboplatin in the dose equivalent to AUC 4.0 mg/ml/min, which is administered immediately after the infusion of gemcitabine on day 1 of each 21 days’ cycle. Dose reduction with each subsequent cycle or during the cycle is possible on the basis of the toxicity level of the drug in patient.

Toxicity monitoring and dose change due to toxicity

Dose adjustment due to non-hematological toxicity

Periodical medical examination shall be performed, as well as renal and liver function monitoring for determination of non-hematological toxicity. Dose reduction with each subsequent cycle or during the cycle is possible on the basis of the toxicity level of the drug in patient. In case of emergence of severe (degree 3 or 4) non-hematological toxicity except for nausea/vomiting the therapist shall withhold the treatment and reduce the drug dose.

Cisplatin, carboplatin and paclitaxel dose adjustment shall be performed according to the instructions for use of the above drugs.

Dose adjustment due to hematological toxicity

Beginning of the cycle

Before each administration of gemcitabine for any indication in patients platelet and granulocyte levels shall be controlled. Before the beginning of the cycle the absolute granulocyte count shall amount to at least 1500x106/l and platelet count – to 100000x106/l.

Throughout the cycle

Gemcitabine dose adjustment throughout the cycle shall be performed according to the tables as follows:

Gemcitabine dose adjustment throughout the cycle in bladder cancer, NSCLC and pancreatic cancer; monotherapy or in combination with cisplatin

Absolute granulocyte count (x106/l)

Platelet count (x106/l)

Percent of the standard dose of gemcitabine (%)

> 1000            and

> 100000

100

500 – 1000      or

50000 – 100000

75

< 500              or

< 50000

withhold administration*

* The withdrawn dose shall not be administered throughout the cycle until the absolute granulocyte count reaches at least 500x106/l and the platelet count – 50000x106/l

 

Gemcitabine dose adjustment throughout the cycle in breast cancer; monotherapy or in combination with paclitaxel

Absolute granulocyte count (x106/l)

Platelet count (x106/l)

Percent of the standard dose of gemcitabine (%)

≥ 1200            and

> 75000

100

1000 ≤ 1200   or

50000 – 75000

75

700 ≤ 1000     and

≥ 50000

50

< 700              or

< 50000

withhold administration*

* The withdrawn dose shall not be administered throughout the cycle until the absolute granulocyte count reaches at least 1500x106/l and the platelet count – 100000x106/l.

Gemcitabine dose adjustment throughout the cycle in ovarian cancer; monotherapy or in combination with carboplatin

Absolute granulocyte count (x106/l)

Platelet count (x106/l)

Percent of the standard dose of gemcitabine (%)

> 1500            and

≥ 100000

100

1000 – 1500    or

75000 – 100000

75

< 1000            or

< 75000

withhold administration*

* The withdrawn dose shall not be administered throughout the cycle until the absolute granulocyte count reaches at least 1500x106/l and the platelet count – 100000x106/l.

Dose adjustment due to hematological toxicity in subsequent cycles for all indications

Gemcitabine dose shall be reduced to 75 % of the initial dose in the cycle in case of emergence of the cases of hematological toxicity as follows:

-           absolute granulocyte count < 500 x 106/l for more than 5 days;

-           absolute granulocyte count < 100 x 106/l for more than 3 days;

-           febrile neutropenia;

-           platelets < 25000 x 106/l;

-           withholding of the cycle for more than 1 week due to toxicity.

Administration

Gemcitabine is well tolerated during the infusion and may be prescribed in an outpatient setting. In case of bleeding the infusion is usually stopped and continued into another blood vessel. The patient is closely monitored after the infusion of the drug.

Special groups of patients

Patients with renal or liver insufficiency

Administer with caution in patients with renal or liver insufficiency due to little information available from clinical trials.

Elderly patients (> 65 years)

Gemcitabine is well tolerated by patients over 65. There is no evidence of necessity of dose adjustment in elderly patients.

Children (< 18 years)

Gemcitabine is not recommended for use in children below 18 due to lack of efficacy and safety data.

Instructions for dissolution (and further dilution, if necessary)

The only acceptable solvent for gemcitabine sterile powder is sodium chloride solution 9 mg/mL (0.9 %) for injections (unpreserved). Due to limited solubility the maximum acceptable concentration during dissolution of gemcitabine amounts to 40 mg/ml. Preparation of gemcitabine solution in concentration of over 40 mg/ml is prohibited due to possibility of incomplete dissolution.

1.         Dissolution and any subsequent dilution of gemcitabine for intravenous injection have to be carried out aseptically.

2.         To dissolve 200 mg of gemcitabine, add 5 ml of sterile sodium chloride solution 9 mg/ml (0.9 %) for injection (unpreserved) into the vial. The final volume after the dissolution: 5.26 ml. The concentration received amounts to 38 mg/ml considering the working volume of the lyophilized powder. Shake until dissolution. Subsequently the solution may be diluted with sterile sodium chloride solution 9 mg/ml (0.9 %) for injection (unpreserved). The solution received shall be transparent, clear or of light straw color.

3.         Before administration check the solution for absence of particulate matter and transparency. Do not use if particulate matter is present.

Contraindications

-           hypersensitivity to gemcitabine or other drug components;

-           pregnancy and lactation.

Adverse effects

The most frequent reports on adverse reactions related to gemcitabine include: nausea with/without vomiting, elevated liver transaminase (AST/ALT) and alkaline phosphatase levels (60 % patients); proteinuria and hematuria (about 50 % patients); dyspnea in 10 – 40 % patients (highest incidence in patients with lung cancer); allergic skin reactions (about 25 % patients) and those with associated itching in 10 % patients.

The frequency and severity of adverse reactions depends on the dose, frequency of infusions and dosage intervals.

Clinical trials results

The incidence of adverse effects is listed in the gradation as follows: very common (> 1/10); common (> 1/100, < 1/10); uncommon (> 1/1000, < 1/100); rare (> 1/10000, < 1/1000); very rare (< 1/10000), including individual reports.

Blood and lymphatic system disorders: very common – leucopenia (3rd degree neutropenia = 19.3%; 4th degree neutropenia = 6%) – bone marrow suppression is usually slightly or moderately expressed and usually effects the granulocytes count; thrombocytopenia; anemia; common – febrile neutropenia; very rare – thrombocytosis.

Immune system disorders: very rare – anaphylactoid reaction.

Metabolism and nutrition disorders: common – anorexia.

Nervous system disorders: common – headache, insomnia, sleepiness.

Cardiac disorders: rare – myocardial infarction, arterial pressure decrease.

Respiratory disorders: very common – dyspnea (usually slight, quickly passing without treatment); common – cough, rhinitis; uncommon – interstitial pneumonia, bronchial spasm (usually slight and transient, though parenteral treatment may be needed).

Gastrointestinal disorders: very common – nausea, vomiting; common – diarrhea, stomatitis and oral cavity ulceration, constipation.

Hepatobiliary disorders: very common – elevated AST and ALT, as well as alkaline phosphatase levels; common – increased bilirubin; rare – increased GGT.

Skin and subcutaneous tissue disorders: very common – allergic skin rush often associated with itching, alopecia; common – itching, sweating; rare – ulceration, vesicles and erosions, peeling; very rare – acute skin reactions including desquamation and vesicular impetigo.

Musculoskeletal and connective tissue disorders: common – back pain, myalgia.

Renal and urinary disorders: very common – hematuria, slight proteinuria.

Other: very common – flu-like symptoms (most common symptoms: fever, headache, chill, myalgia, asthenia and anorexia; cough, rhinitis, ailment, sweating and insomnia were reported, as well), edema/peripheral edema including facial edema (edema usually passes after withdrawal of therapy); common – fever, asthenia, chill; rare – local response to administration (usually slight).

Injury, poisoning and procedural complications: adverse effect of radiation therapy during subsequent chemotherapy.

Postclinical experience (adverse events reports). Unspecified frequency (impossible to assess from available data)

Nervous system disorders: cerebrovascular disease.

Cardiac disorders: arrhythmia, heart failure, predominantly of supraventricular nature, clinical symptoms of peripheral vasculitis and gangrene.

Respiratory, thoracic and mediastinal disorders: pulmonary edema, adult respiratory distress syndrome.

Gastrointestinal disorders: ischemic colitis.

Hepatobiliary disorders: acute hepatotoxicity including liver failure and death.

Skin and subcutaneous tissue disorders: acute skin reactions including desquamation and vesicular impetigo, Lyell’s disease, Stevens-Johnson syndrome.

Renal and urinary disorders: renal failure, hemolytic-uremic syndrome.

Injury, poisoning and procedural complications: adverse effect of radiation therapy during subsequent chemotherapy.

Combined therapy in breast cancer. Incidence of hematological toxicity of the 3rd and the 4th degree, especially that of neutropenia, increases in prescribing gemcitabine with paclitaxel. However, frequent cases of these adverse reactions are not related to increased incidence of infection and hemorrhagic complications. Fatigue and febrile neutropenia occur more frequently in combined administration of gemcitabine with paclitaxel. Fatigue not associated with anemia usually disappears after the first cycle.

Adverse events of the 3rd and the 4th degree in paclitaxel therapy vs. gemcitabine/paclitaxel combination

 

Number (%) of patients

Paclitaxel

Gemcitabine/paclitaxel

Degree 3

Degree 4

Degree 3

Degree 4

Laboratory values

Anemia

5 (1.9)

1 (0.4)

15 (5.7)

3 (1.1)

Thrombocytopenia

0

0

14 (5.3)

1 (0.4)

Neutropenia

11 (4.2)

17 (6.6)*

82 (31.3)

45 (17.2)*

General symptoms

Febrile neutropenia

3 (1.2)

0

12 (4.6)

1 (0.4)

Fatigue

3 (1.2)

1 (0.4)

15 (5.7)

2 (0.8)

Diarrhea

5 (1.9)

0

8 (3.1)

0

Motor neuropathy

2 (0.8)

0

6 (2.3)

1 (0.4)

Sensory neuropathy

9 (3.5)

0

14 (5.3)

1 (0.4)

* 4th degree neutropenia within 7 days occurred in 12.6% patients receiving combined therapy and in 5% patients receiving paclitaxel.

 

Combined therapy in bladder cancer

 

Adverse events of the 3rd and the 4th degree in MVAC therapy vs. gemcitabine/cisplatin combination

 

Number (%) of patients

MVAC (methotrexate, vinblastine, doxorubicin and cisplatin)

Gemcitabine/cisplatin

Degree 3

Degree 4

Degree 3

Degree 4

Laboratory values

Anemia

30 (16)

4 (2)

47 (24)

7 (4)

Thrombocytopenia

15 (8)

25 (13)

57 (29)

57 (29)

General symptoms

Nausea and vomiting

37 (19)

3 (2)

44 (22)

0 (0)

Diarrhea

15 (8)

1 (1)

6 (3)

0 (0)

Infection

19 (10)

10 (5)

4 (2)

1 (1)

Stomatitis

34 (18)

8 (4)

2 (1)

0 (0)

 

Combined therapy in ovarian cancer

 

Adverse events of the 3rd and the 4th degree in carboplatin therapy vs. gemcitabine/carboplatin combination

 

Number (%) of patients

Carboplatin

Gemcitabine/carboplatin

Degree 3

Degree 4

Degree 3

Degree 4

Laboratory values

Anemia

10 (5.7)

4 (2.3)

39 (22.3)

9 (5.1)

Neutropenia

19 (10.9)

2 (1.1)

73 (41.7)

50 (28.6)

Thrombocytopenia

18 (10.3)

2 (1.1)

53 (30.3)

8 (4.6)

Leucopenia

11 (6.3)

1 (0.6)

84 (48.0)

9 (5.1)

General symptoms

Bleeding

0 (0)

0 (0)

3 (1.8)

0 (0)

Febrile neutropenia

0 (0)

0 (0)

2 (1.1)

0 (0)

Infection without neutropenia

0 (0)

0 (0)

0 (0)

1 (0.6)

Cases of sensory neuropathy were also more frequent in combined therapy than in therapy with carboplatin.

Overdosage

No gemcitabine antidote exists. In case of intravenous administration within 30 minutes of doses exceeding 5700 mg/m2 every two weeks clinically acceptable toxicity was observed. In case overdosage is suspected, the patient shall be under constant medical control including blood count monitoring. If needed, supporting therapy is conducted.

Special precautions

In case of increased infusion time and administration frequency the toxicity of gemcitabine grows.

Hematological toxicity

Gemcitabine can suppress the bone marrow function which manifests through leucopenia, thrombocytopenia and anemia.

In patients receiving gemcitabine treatment thrombocyte, leucocyte and granulocyte counts shall be determined before each prescription. In case of therapy-related inhibition of bone marrow function the treatment shall be withheld and the drug dose shall be adjusted. However, myelosuppression is short-term and usually does not require dose reduction and rarely leads to treatment withdrawal.

The amount of peripheral blood may continue to decrease after gemcitabine withdrawal. In patients with bone marrow function disorder the treatment shall be initiated with caution. In case of concomitant use of gemcitabine with another chemotherapy the possible risk of cumulative inhibitory effect of bone marrow shall be considered.

Liver failure

Prescription of gemcitabine to patients with metastases in liver or with history of hepatitis, alcoholism or liver cirrhosis may lead to exacerbation of liver failure.

Liver and kidney functions shall be assessed from time to time (including virological tests).

Gemcitabine shall be administered with caution in patients with liver and kidney failure, as the clinical trials did not provide sufficient information for dosing in this category of patients.

Concomitant radiation therapy

Occurrence of toxicity in radiation therapy together with gemcitabine or with the interval of ≤ 7 days was reported.

Live vaccines

Patients receiving treatment with gemcitabine are not recommended vaccination against yellow fever or administration of other live attenuated vaccines.

Cardiovascular diseases

Patients with history of cardiovascular diseases have to take care when treated with gemcitabine due to the risk of development of cardiac and/or vascular disorders.

Respiratory system

During treatment with gemcitabine adverse reactions from the part of the respiratory system were reported; some of them being severe (pulmonary edema, interstitial pneumonia or adult respiratory distress syndrome (ARDS)). In case of occurrence of the above reactions withdrawal of therapy shall be considered. Early conduction of supporting therapy may improve the patient’s condition.

Urinary system

Several cases of occurrence of hemolytic-uremic syndrome (HUS) in patients receiving gemcitabine were described in clinical trials. At the occurrence of the first indications of microangiopathic hemolytic anemia (abrupt drop of hemoglobin level with associated thrombocytopenia, increased bilirubin in blood plasma, plasma creatinine, blood urea nitrogen or lactate dehydrogenase) treatment with gemcitabine must be immediately withdrawn. In case renal failure persists after withdrawal of therapy dialysis may be needed.

Sodium

Gemcitabine 200 mg contains 3.5 mg (< 1 mM) sodium per vial. This shall be considered when prescribing the drug to patients on sodium diet.

Drug interaction

Radiation therapy

Concomitant (simultaneous or with the interval of ≤ 7 days) – toxicity related to multimodal therapy depends on the parameters as follows: gemcitabine dose, gemcitabine administration frequency, radiation dose, radiation therapy planning method, target organ and target volume of radiation exposure. The clinical and preclinical trials demonstrate the radiosensibilising action of gemcitabine. The clinical trial where gemcitabine was administered for 6 weeks in a row simultaneously with the radiation therapy of the chest in NSCLC patients showed toxicity manifesting as acute, potentially life-threatening mucositis, in particular, esophagitis and pneumonia, especially in patients with high radiation exposure (mean volume is 4795 cm3). In subsequent NSCLC trials it was determined that gemcitabine in lower doses can be used in combination with radiation therapy. Irradiation of the chest in the dose of 66 Gray was carried out in combination with gemcitabine administration (600 mg/m2 x 4) and cisplatin (80 mg/m2 x 2) for 6 weeks. There is no optimum dosing regimen for gemcitabine for safe combined use with therapeutic doses of radiation therapy for all tumor types today.

Differential (interval > 7 days) – no hypertoxicity was determined when administering gemcitabine with the interval of more than 7 days before or after radiation therapy, except for the irradiation effect itself. Gemcitabine administration can be initiated immediately after the passing of acute adverse reactions to radiation therapy or at least in a week after the end of the radiation therapy.

Radiation damage to target organs (e.g., esophagitis, colitis and pneumonia) occurred both with concomitant administration of gemcitabine and with differential radiation therapy.

Other

Patients receiving treatment with gemcitabine are not recommended vaccination against yellow fever or administration of other live attenuated vaccines due to the risk of systemic diseases with possibility of lethal outcome (especially in immunosuppressive patients).

Use during pregnancy and lactation

Pregnancy

There is no sufficient data on administration of gemcitabine in pregnant women. Anima l studies demonstrated reproductive toxicity. On the grounds of the preclinical trials data and the mode of action of gemcitabine, the drug is not recommended for use during pregnancy, except for cases of special necessity. Women of childbearing age must use reliable methods of contraception during treatment with gemcitabine and immediately warn their therapist in case of pregnancy.

Lactation period

There is no data on possibility of gemcitabine permeating the breast milk. The adverse reactions the drug may cause while getting into the child’s body with mother’s milk are also unknown. Breast feeding must be discontinued for the period of treatment with gemcitabine.

Reproductive toxicity

In trials administration of gemcitabine in male mice caused hypospermatogenesis. For this reason, men receiving gemcitabine treatment must use effective methods of contraception during the therapy and for 6 months after its end. The patients are encouraged to receive additional advice on sperm cryopreservation before the beginning of treatment, as there is the possibility of infertility due to gemcitabine treatment.

Effects on ability to drive or use potentially dangerous mechanisms. Gemcitabine’s effect on ability to drive or use potentially dangerous mechanisms was not studied. However, judging by the ability of gemcitabine to case slight sleepiness (especially with simultaneous alcohol intake) the patient should avoid driving or using potentially dangerous mechanisms for the period of treatment with gemcitabine.

Pharmaceutical form

200 mg in 10 ml vials stoppered with rubber stoppers and rolled with aluminum or alumoplastic caps. Each vial together with instructions for use is placed into the carton pack.

Storage

Store in protected from light place at temperature below 25 °C.

Keep out of reach of children.

Shelf life

2 years.

Do not use after expiration date stated on the package.

Prescription status

On prescription.

Manufacturer

“Belmedpreparaty” RUE,

Republic of Belarus,

Minsk, 220007,

30, Fabritsius str.