INSTRUCTION

for medical use of the preparation

GEMATIX

Composition:

Active substance: gemcitabine;

1 vial contains gemcitabine hydrochloride equivalent to gemcitabine 200 mg;

Auxiliary substances: mannitol (Е 421), sodium acetate, sodium hydroxide, hydrochloric acid.

Medical form. Lyophilizate for preparation of the solution for infusions.

Pharmacotherapeutical group.

Antineoplastic agents. Structural analogues of pyrimidine. АТС code L01B C05.

Clinical characteristics.

Indications.

• Urinary bladder cancer. Gemcitabine is indicated for treatment of locally spread or metastatic urinary bladder cancer in combination with cisplatin.

• Pancreas cancer. Gemcitabine is indicated for treatment of locally spreadadronocarcenoma of pancreatic gland.

• Non-small cell lung cancer. Gemcitabine is indicated in combination with cisplatin as a first line therapy in patients with locally progressing or metastatic non-small cell lung cancer. The possibility of gemcitabine monotherapy use may be considered for elderly patients or for patients having functional status 2 according to ECOG scale.

• Ovary cancer. Gemcitabine in combination with carboplatin is indicated for treatment of locally spread or metastatic epithelial ovary cancer in patient with recurrent disease after recurrence-free period, which lasted for at least 6 months, after first-line therapy with platinum praparations.

• Breast cancer. Gemcitabine in combination with paclitaxel is indicated for treatment of patients with inoperable locally recurrent or metastatic breast cancer, who developed a recurrence after previous adjuvant/non-adjuvant chemotherapy. Previous chemotherapy in case of exclusion of clinical contraindications should include anthracyclines.

Contraindications.

Hypersensitivity to gemcitabine or other components of the preparation.

Way of administration and doses.

Gemcitabine may be indicated only by the doctor already having experience of anticancerchemotherapy administration.

Way of administration

For intravenous intoduction.

Gemcitabine infusions are tolerated well by the patients, so it can be introduced in out-patient conditions. In case of extravasation development, the infusion is discontinued immediately and the introduction of the preparation should be continued into another vein. After gemcitabine introduction, the patient should be staying under careful monitoring.

Way of preparation of the solution for infusion. See “Instruction for preparation of the solution”.

Adults

Urinary bladder cancer

Combined administration

The recommended dose of gemcitabine is 1,000 mg/m² to be introduced via intravenous 30-minute infusion. This dose should be administrated on Days 1, 8 and 15 of every 28-day circle in combination with cisplatin. Cisplatin is introduced in the recommended dose 70 mg/m² on Day 1 after gemcitabine or on Day 2 of every 28-day circle. Then this 4-week circle is repeated. Decrease in the dose with every circle or during any single circle is possible due to the patient’s toxicity degree.

Pancreas cancer

Gemcitabine should be introduced via intravenous infusion in the dose of 1000 mg/m²during 30 minutes once a week for 7 weeks with further 1-week interval. The following circles should be infusions that are conducted once a week for 3 weeks with further interval every 4^th week. Before initiation of every new circle or during any single circle conduction, dose adjustment is possible due to the patient’s toxicity degree.

Non-small cell lung cancer

Monotherapy

The recommended dose of gemcitabine is 1,000 mg/m² and is introduced via 30-minute intravenous infusion once a week for 3 weeks with further 1-week interval. This 4-week circle is repeated. Decrease in the dose with every circle or during any single circle is possible due to the patient’s toxicity degree.

Combined therapy with cisplatin

The recommended dose of gemcitabine is 1,250 mg/m² of body surface and is introduced via 30-minute intravenous infusion on Days 1 and 8 of the circle (21 days). Before initiation of every new circle or during any single circle conduction, dose adjustment is possible due to the patient’s toxicity degree. Cisplatin was administrated in the dose of 75–100 mg/m² once every 3 weeks.

Breast cancer

Combined administration

Gemcitabine in combination with paclitaxel is recommended for introduction in the following regimen: paclitaxel (175 mg/m) is introduced on Day 1 during 3-hour intravenous infusion, then gemcitabine (1,250 mg/m²) is introduced during 30-minute intravenous infusion on Days 1 and 8 of each 21-day circle. Before initiation of every new circle or during any single circle conduction, dose adjustment is possible due to the patient’s toxicity degree. Patient should have absolute granulocyte count, at least 1.500 (´ 10/L), before treatment initiation with combination of gemcitabine + paclitaxel.

Ovary cancer.

Combined administration

Gemcitabine in combination with carboplatin is recommended for introduction in the dose of 1,000 mg/m via 30-minute intravenous infusion on Days 1 and 8 of each 21-day circle. On Day 1 of the circle after gemcitabine, carboplatin is introduced in the dose necessary to provide AUC equal to 4 mg/ml/min. Before initiation of every new circle or during any single circle conduction, dose adjustment is possible due to the patient’s toxicity degree.

Monitoring of toxicity phenomena and dose adjustment of the preparation

Dose adjustment due to phenomena of non-hematologic toxicity

In order to control non-hematologic toxicity, it is necessary to conduct regular patient examination and estimate their hepatic and renal functions. The dose of gemcitabine may be decreased (for all courses or within any one course) due to intensity of toxicity phenomena. Generally, in case of development of severe (degree 3 or 4) phenomena of non-hematologic toxicity, excluding nausea/vomiting, gemcitabine therapy is discontinued or the dose of the preparation is decreased due to doctors’ indications. Treatment with gemcitabine can be continued only after toxicity effects resolve.

Dose adjustment due to phenomena of hematologic toxicity

At the beginning of the treatment course

Irrespectively to indications, before every introduction of the preparation it is necessary to estimate the count of platelets and granulocytes in blood. The treatment can be initiated if granulocyte count is ≥1,500 (x 10⁶/l), and platelet count is ≥ 100,000 (x 10⁶/l).

During the treatment course

Gemcitabine dose adjustment is carried out according to the recommendations given below.

Table 1

Gemcitabine dose adjustment during the course of treatment in patients with urinary bladder cancer, non-small cell lung cancer or pancreas cancer in monotherapy or combined therapy with cisplatin.

Absolute granulocyte count (х106/L)	Platelet count (х106/L)	Per cent of usual gemcitabine dose, %
> 1 000 and	> 100,000	100
500-1,000 or	50,000-100,000	75
<500 or	< 50,000	Skipping the dose*

* Continued introduction of gemcitabine within the course is possible only after achievement of absolute granulocyte count ≥500 (x10⁶/L) and platelet count ≥50 000 (x10⁶/L).

Table 2

Gemcitabine dose adjustment during the course of treatment in patients with breast cancer in combined therapy with paclitaxel

Absolute granulocyte count (х106/L)	Platelet count (х106/L)	Per cent of usual gemcitabine dose, %
≥ 1,200 and	> 75,000	100
1,000- <1,200 or	50,000-75,000	75
700- <1,000 and	≥ 50,000	50
<700 or	< 50,000	Skipping the dose *

* Treatment within the course cannot be renewed. The therapy is initiated on Day 1 of the following course if absolute granulocyte count is ≥1,500 (x10⁶/L) and platelet count is ≥100,000 (x10⁶/L).

Table 3

Gemcitabine dose adjustment during the course of treatment in patients with ovary cancer in combined therapy with carboplatin

Absolute granulocyte count (х106/L)	Platelet count (х106/L)	Per cent of usual gemcitabine dose, %
> 1,500 and	≥ 100,000	100
1,000-1,500 or	75,000-100,000	50
<1,000 or	< 75,000	Skipping the dose *

* Treatment within the course cannot be renewed. The therapy is initiated on Day 1 of the following course if absolute granulocyte count is ≥1,500 (x10⁶/L) and platelet count is ≥100,000 (x10⁶/L).

 

Change of the dose due to development of hematologic toxicity in the following cycles, for all indications

Gemcitabine dose should be decreased by 75% as for initial dose of the cycle in case of development of the following manifestations of hematologic toxicity:

• absolute granulocyte count < 500 x 10⁶/L for more than 5 days;

• absolute platelet count < 100 x 10⁶/L for more than 3 days;

• febrile neutropenia;

• platelet < 25000 x 10⁶/L;

• cycle postponement for more than 1 week due to toxicity development.

Rules of preparation of the solution for infusion.

The only allowed solvent for reconstitution of gemcitabine sterile powder is sodium chloride solution for injection 9 mg/ml (0.9 %) (without preservatives). Taking into consideration the solubility, maximal concentration of gemcitabine after reconstitution is 40 mg/ml. Reconstitution in concentrations exceeding 40 mg/ml may be the reason of incomplete dissolution and should be avoided.

1. During dissolution and further dilution gemcitabine for intravenous introduction via infusion, aseptic method is used.

2. For dissolution, add 5 ml of the sterile solution for infections of sodium chloride 9 mg/ml (0.9 %), which does not contain preservatives, to the vial containing gemcitabine 200 mg. Total volume after dissolution is 5.26 ml. Thus, the obtained solution has a concentration of 38 mg/ml, which takes into account the volume of freeze-dried powder substitution. Shake the vial for dissolution. Further diluting can be carried out with the sterile solution for infections of sodium chloride 9 mg/ml (0.9 %), which does not contain preservatives. The obtained solution is a transparent colorless or pale yellow solution.

3. Prior introduction medicinal preparations for parenteral administration should undergo visual assessment for presence of mechanical admixtures and change of the color. In case of presence of any mechanical admixtures, the solution should not be introduced.

Unused preparation or material waste should be utilized according to local requirements.

Side effects.

From the side of blood system: suppression of bone marrow blood formation (anemia, leukopenia, neutropenia, thrombocytopenia); very seldom – thrombocytosis, febrile neutropenia.

From the side of gastrointestinal tract: nausea, vomiting, anorexia, diarrhea, constipation, stomatitis, increased serum levels of hepatic enzymes.

From the side of liver and bile-excreting tracts: increased levels of hepatic tests, such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), alkaline phosphatase and bilirubin have been reported seldom.

From the side of urinary tracts: proteinuria, hematuria, renal insufficiency; in single cases – symptoms similar to hemolytic uremic syndrome. Renal disorders may be irreversible even after treatment determination (hemodialysis may be necessary). Treatment with gemcitabine should be discontinued in case of development of first signs of microangiopathic hemolytic anemia, such as abrupt decrease of hemoglobin level with concomitant thrombocytopenia and increased serum levels of bilirubin, creatinine, urea and/or lactate dehydrogenase.

Dermatological reactions: skin rash, which is accompanied by itching, partial alopecia, and erythema; very seldom – desquamation, bullous rash, vesicle and ulcer on skin.

From the side of respiratory system: dyspnea, cough; seldom – bronchospasm, interstitial pneumonia, pulmonary edema, respiratory distress syndrome. In case of development of these symptoms, the treatment with gemcitabine should be discontinued.

From the side of cardiovascular system: peripheral edema; in single cases – arterial hypotension, myocardial infarction, arrhythmia, cardiac insufficiency; very seldom – peripheral vasculitis, gangrene.

From the side of nervous system: sleep disorders, sleepiness.

Changes in laboratory indexes: increased serum levels of bilirubin, gamma-glutamyl transferase, creatinine, urea, lactate dehydrogenase, and alkaline phosphatase.

From the side of the organism in general: fungi-like symptoms, such as fever, headache, chill, myalgia, asthenia; cough, rhinitis, malaise, and hyperhidrosis are possible; radiation toxicity (in case of concomitant radiotherapy).

Allergic reactions: seldom – anaphylactic reactions.

Combined administration for breast cancer

The frequency of hematological toxicity of degree 3 and 4 (neutropenia, thrombocytopenia, leukopenia, anemia) increases, when gemcitabine is used in combination with paclitaxel. However, increased frequency of undesirable phenomena is not associated with increased frequency of infections or hemorrhagic complications. Fatigue and fibril neutropenia are observed more often, if gemcitabine is used in combination with paclitaxel. Fatigue, which is not connected with anemia, usually dissolves after the first cycle of the therapy.

Overdose.

Overdose is manifested by increased toxic action. Clinically acceptable toxicity has been observed in case of gemcitabine introduction as single intravenous doses up to 5.7 g/m²for 30 minutes every 2 weeks. As soon as overdosing is suspected, the patient should be provided constant medical supervision, including blood count control. If necessary, symptomatic therapy is indicated. There is no specific antidote.

Use during pregnancy and lactation.

The use of the preparation is contraindicated during pregnancy and lactation period.

Children.

The preparation is not used in pediatric practice due to the lack of clinical experience.

Special safety measures.

Preventive measures while working with the preparation Gematix.

During preparation and utilization of the solution for infusions, it is necessary to follow standard safety measures for cytostatic preparations. Any actions with the solution for infusions should be carried out in the protected container, wearing protective clothes and gloves. If there is no protected container, safety means should be supplemented with a mask and protective eye glasses.

If the solution gets into eyes, serious irritation is possible. In this case the eyes should be washed immediately and thoroughly with water. If the symptoms of irritation preserve, it is necessary to turn to the doctor. If the solution gets onto the skin, it should be rinsed thoroughly with water.

Peculiarities of the use.

Increased time of infusion and increased dose frequency has demonstrated increased toxicity.

Hematologic toxicity

Gemcitabine may suppress the function of bone marrow, which is manifested by leukopenia, thrombocytopenia and anemia. Before every introduction of the preparation, it is necessary to control platelet, leukocyte and granulocyte counts. In case of development of medicamentous myelosupression, it is necessary to discontinue the treatment or decrease the dose of the preparation. Usually myelosupression during gemcitabine treatment is short-coming and seldom requires withdrawal of the preparation. Increasing of cytopenia may also preserve after withdrawal of gemcitabine. The preparation should be indicated with caution in patients with disturbed function of bone marrow. It is necessary to take into consideration the risk of cumulative myelosupression in case of combined chemotherapy with gemcitabine and other cytostatic preparations.

Hepatotoxicity

Gemcitabine use in patients with hepatic metastases as well as with history of hepatitis, alcohol dependence or liver cirrhosis may cause worsening of present liver insufficiency.

In case of treatment with gemcitabine, it is necessary to control periodically liver function (including conduction of virology analyses).

Gemcitabine should be indicated with caution in patients with disturbed hepatic function or with disturbed renal function due to insufficient data of clinical research as for exact dosing for these group of patients.

Cardiovascular toxicity

Due to the risk of development of cardiac and vascular disorders, the preparation should be indicated with caution in patients with history of cardiovascular diseases.

Pulmonary toxicity

There have been reports on the development of side effects from the side of respiratory system, sometimes severe (pulmonary edema, interstitial pneumonia and respiratory distress syndrome in adults) during treatment with gemcitabine. Etiology of these effects has not been established yet. In case of development of these phenomena, it is necessary to consider the appropriateness of gemcitabine treatment discontinuation. Early initiation of supportive therapy provides the possibility to improve the state of the patient.

Renal toxicity

During treatment with gemcitabine, it is necessary to conduct periodical control of renal function.

In case of development of first signs of microangiopathic hemolytic anemia (abrupt decrease of hemoglobin level with concomitant thrombocytopenia and increased serum levels of bilirubin, creatinine, urea nitrogen or lactate dehydrogenase), the preparation should be discontinued. Renal insufficiency may be irreversible after gemcitabine withdrawal, and the patient may require hemodialysis.

Sodium

This medicinal preparation contains sodium. It should be considered in patients, who follow controlled sodium diet.

Ability to influence the reaction rate when driving or operating other mechanisms.

During treatment it is recommended to avoid potentially dangerous types of activity that require increased attention as well as psychic and locomotive reaction rate.

Interaction with other medicinal preparations and other forms of interactions.

Concomitant radiotherapy (together or during first 7 days after gemcitabine introduction): toxicity, caused by the therapy with different methods, depends on various factors, including gemcitabine dose, infusion frequency, radiation dose, scheme of radiotherapy conduction, scheduled technique, zone and volume of radiation.

Research studies have shown that gemcitabine has radiosensitization activity. When gemcitabine was indicated in the dose of 1000 mg/m² during the period up to 6 weeks together with therapeutic irradiation of the thoracic cage in patients with non-small cell lung cancer, there was observed a significant toxicity as severe and potentially life-threatening mucositis, esophagitis and pneumonitis, especially in patients treated with large-volume radiotherapy (volume of median treatment of 4795 cm³).

In case of non-small cell lung cancer, the appropriateness of gemcitabine administration in smaller doses in combination with radiotherapy with forecasted toxicity has been proved. Irradiation of the thoracic cage in the doses of 66 Gy was conducted in combination with gemcitabine (600 mg/m², four times) and cisplatin (80 mg/m², twice) for 6 weeks. The optimal regimen of safe gemcitabine use with therapeutic doses of irradiation for all tumor types has not been established yet.

Non-concomitant radiotherapy (> 7 days): data analysis has not revealed increased toxicity in case of gemcitabine administration over 7 days before or after irradiation. Data demonstrate that gemcitabine use may be initiated as soon as acute outcomes of irradiation resolve or at least in one week after radiotherapy.

There have been reports about tissue lesions after radiotherapy (for example, esophagitis, colitis and pneumonitis) in case of both concomitant and non-concomitant indication of gemcitabine.

Pharmacological properties.

Pharmacodynamics. Gemcitabine is antitumor preparation, which has cytotoxic action conditioned by inhibition of DNA synthesis. The preparation is metabolized in the cell to active biphosphate and triphosphate nucleosides. Biphosphate nucleosides, which have been formed, in the first place inhibit the action of ribonucleotide reductase. This enzyme catalyzes reactions, which lead to the formation of deoxynucleosidyl triphosphates for DNA synthesis, which leads to their decreased concentration in the cell. In the second place, triphosphate nucleosides, which have been obtained during metabolism of the preparation, compete actively for inclusion into DNA chain, as well as the may be also included into RNA. After introduction of intracellular metabolites of the preparation into DNA chain, one additional nucleotide is added to its growing chains, which leads to total inhibition of further DNA synthesis and programmed death of the cell.

Pharmacokinetics. After single infusion of the preparation in the dose of 1 g/m² for 30 minutes, maximal plasma concentration of gemcitabine is achieved in 3-15 minutes after the end of the infusion. Binding of the preparation with plasma proteins is very low. The volume of its distribution in tissues is insignificant and on average is 11 L/m². The preparation is metabolized in the cells of liver, kidneys, blood and other tissues of the organism with an enzyme called cytidine deaminase stage-by-stage until inactive uracil metabolite is formed. During the process of intracellular metabolism, active biphosphate and triphosphate nucleosides are formed. Intracellular concentration of nucleosides increases proportionally to plasma concentration of the preparation. As soon as equilibrial plasma concentration of gemcitabine over 5 µg/ml is achieved, intracellular concentration of nucleosides does not increase any longer. After infusion gemcitabine administration for 30 minutes in the dose of 1 g/m², its plasma concentration will be approximately 5-4 µg/ml for 1.5 hours, which provides sufficient concentration of nucleosides within the cell. Intracellular metabolites in plasma and urine are not detected. The preparation is excreted mainly as uracil metabolite (mainly with urine, less than 1 % – with feces); 1 % of the doses is excreted in unchanged state with urine. Its half-life is almost 17 minutes. In case of multiple administrations this index increases slightly. In women the clearance of the preparation is somewhat lower than in men. Kinetic studies of the preparation in patients with renal or hepatic insufficiency have not been conducted. It is expected that in case of decreased renal function, inactive metabolite may be accumulated in the organism.

Pharmaceutical characteristics.

Main physical and chemical properties: powder of white or almost white color.

Incompatibility. Do not mix or use concomitantly with other preparations in one and the same infusion system.

Shelf life. 2 years.

Not to be used after expiration date indicated on the package.

Conditions of storage.

Store at temperature below 25 °С in the original package. Keep out of the reach of children. Do not freeze.

Package. 1 vial with the preparation in a carton.

Category of dispensing. On prescription.

Manufacturer. Marksans Pharma Ltd.

Location.

Juridical address: Floor 21, Lotus Business Park, Off New Link Road, Andheri (West), Mumbai – 400053, India;

Address of the manufacturing site: Village Asahfdfl, Dudhia, Indor – 453 331, India.

Applicant. Ananta Medicare Ltd.

Location. Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, United Kingdom

Date of the last review. 09.08.2011.