SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

[XXX] 200 mg powder for solution for infusion [XXX] 1 g powder for solution for infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

[For 200 mg strength:] Each vial contains 200 mg (as hydrochloride).

Excipient: Each vial contains 3.5 mg sodium.

[For 1 g strength:] Each vial contains 1 g gemcitabine (as hydrochloride).

Excipient: Each vial contains 17.5 mg sodium.

One ml of the reconstituted solution for infusion contains 38 mg gemcitabine (as hydrochloride).

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Powder for solution for infusion.

White to off-white lyophilized cake.

The pH of the reconstituted solution is between pH 2.7 - 3.3.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications.

Bladder cancer: Treatment of locally advanced or metastatic bladder cancer, in combination with .

Breast cancer: Treatment of locally advanced or metastatic breast cancer in combination with in patients experiencing a relapse after (neo)adjuvant . Prior chemotherapy should have included an , unless clinically contra-indicated.

Non-small cell lung cancer: Treatment of locally advanced or metastatic non-small cell lung cancer, in monotherapy or in combination with cisplatin.

Pancreatic cancer: Treatment of locally advanced or metastatic adenocarcinoma of the pancreas in patients who are in good general condition and with sufficient marrow reserves.

4.2 Posology and method of administration

Upon reconstitution a colourless solution is the product.

Treatment of gemcitabine should be started by, or in consultation with, a physician with considerable experience of cytotoxic medicinal products treatment (see also section 6.6 “Guidelines for the safe handling”).

Bladder cancer (combination therapy): Adults: The recommended gemcitabine dose is 1000 mg/m2, given as a 30-minute infusion. The dose should be given on days 1, 8 and 15 of each 28-day treatment cycle in combination with cisplatin. Cisplatin is given at a recommended dose of 70 mg/m2 on day 2 of each 28-day treatment cycle. This 4-week cycle is subsequently repeated. Depending on the amount of toxicity observed in the patient, the dose can be reduced between treatment cycles or within an existing cycle.

Breast cancer (combination therapy): Adults: The following dosing regimen is recommended for the gemcitabine + paclitaxel combination: Paclitaxel (175 mg/m2) is intravenously infused over 3 hours on day 1 followed by gemcitabine1250 mg/m2 intravenously infused for 30 minutes on days 1 and 8 of each 21-day treatment cycle. Depending on the amount of toxicity observed in the patient, the dose can be reduced between treatment cycles or within an existing cycle. Prior to use of the gemcitabine + paclitaxel combination, the patient should have an absolute granulocyte count of at least 1.5 x 109/l.

Non-small cell lung cancer (combination therapy): Adults: For the gemcitabine + cisplatin combination, the application of two dosing regimens has been investigated; one regimen with a three-week treatment cycle and the other with a four-week cycle.

During the three-week treatment cycle, the gemcitabine dose is 1250 mg/m2, given by 30-minute intravenous infusion, on days 1 and 8 of each 21-day cycle. Depending on the amount of toxicity observed in the patient, the dose can be reduced between treatment cycles or within an existing cycle.

During the four-week treatment cycle, the gemcitabine dose is 1000 mg/m2, given by 30 minute intravenous infusion, on days 1, 8 and 15 of each 28-day cycle. Depending on the amount of toxicity observed in the patient, the dose can be reduced between treatment cycles or within an existing cycle.

Cisplatin has been used at doses between 75-100 mg/m2 once every 3 or 4 weeks.

Non-small cell lung cancer (mono therapy): Adults: The recommended dose of gemcitabine is 1000 mg/m2, given by 30 minute intravenous infusion. This should be repeated once weekly for three weeks, followed by a one week rest period. This four-week cycle is then repeated. Dosage reduction is applied based upon the amount of toxicity experienced by the patient.

Pancreatic cancer: Adults: The recommended gemcitabine dose is 1000 mg/m2, given as a 30-minute infusion. This should be repeated once weekly for up to 7 weeks, followed by one week of rest. For subsequent treatment cycles, a once-weekly infusion should be given for a period of three consecutive weeks, followed by one week of rest. Depending on the amount of toxicity observed in the patient, the dose can be reduced between treatment cycles or within an existing cycle.

Monitoring, adjustment or dose escalation and end of treatment: Prior to each dose, patients must be monitored for , leukocyte, and granulocyte counts (see section 4.4). If necessary, at the onset of any haematological effects, the dose must be reduced or treatment temporarily suspended. Reductions in the gemcitabine dose on days 8 and/or 15 due to toxicity should take place in accordance with the guidelines given in Tables 1-2 below.

Table 1: Adjustment of the gemcitabine dose on days 8 and/or 15 in cases of bladder cancer, non- small cell lung cancer and pancreatic cancer

Absolute granulocyte count (x109/l) Platelet Dosage count (x 109/l) > 1 and > 100 100% of the normal dose 0.5 – 1 or 50 – 100 75% of the normal dose < 0.5 or < 50 Discontinuation of treatment*

Table 2: Adjustment of the gemcitabine dose on day 8 in patients with breast cancer

Absolute granulocyte count (x109/l) Platelet Dosage count (x 109/l) ≥1.2 and > 75 100% of the normal dose 1 - < 1.2 or 50 – 75 75% of the normal dose 0.7 - <1 and ≥ 50 50% of the normal dose < 0.7 or < 50 Discontinuation of treatment*

* Treatment can be continued on day 1 of the next treatment cycle.

At the onset of the following haematological toxic effects, the dose for subsequent treatment cycles should be gradually titrated by one dose level (see Table 3).

• absolute neutrophil count <0.5 x 109/l for more than 5 days • absolute neutrophil count <0.1 x 109/l for more than 3 days • febrile neutropenia, i.e. temperature ≥38°C, absolute neutrophil count <1.0 x 109/l, necessitating hospitalisation and use of an intravenous . • <25 x 109/l • > 1-week postponement of subsequent treatment cycle due to toxicity.

Table 3: Dose levels for gemcitabine and

Dose level 0 - 1 - 2 1000 mg/m2 on days 800 mg/m2 on days 800 mg/m2 on day 1 Gemcitabine 1 and 8 1 and 8 Carboplatin AUC 4.0 on day 1 AUC 4.0 on day 1 AUC 4.0 on day 1

During treatment with gemcitabine, hepatic and renal function, as well as transaminase (AST/ALT) and serum creatinine levels, must be regularly monitored for non-haematological toxicity. Depending on individual tolerance, the dose can be reduced during the existing treatment cycle or the following cycle. The reduced dose should be given until toxicity begins to recede.

Elderly patients: Gemcitabine has been well tolerated in patients over the age of 65. There is no evidence to suggest that dose adjustments are necessary in the elderly, although Gemcitabine clearance and half-life are affected by age.

Children: Safety and efficacy of gemcitabine in children has not been established, therefore its use is not recommended.

Patients with impaired hepatic or renal function: Gemcitabine should be used with caution in patients with hepatic or renal impairment. Studies have been performed in patients with moderate hepatic or renal impairment, dose adjustment was not needed. There are no data available in case of severe impairment (see sections, 4.4 and 4.8).

Administration: Gemcitabine should be reconstituted and diluted afterwards before use (see section 6.6). Gemcitabine is well tolerated during the infusion, with only a few cases of injection site reaction reported and can be administered on an outpatient basis.

4.3 Contraindications

• Hypersensitivity to the active substance (gemcitabine) or to any of the excipients. • Use during breast-feeding. • Concomitant administration of yellow fever (see sections 4.5 and 4.8).

4.4 Special warnings and precautions for use

General:

Treatment with gemcitabine should be started by, or in consultation with, a physician with considerable experience in the use of cytotoxic medicinal products. Patients receiving therapy with Gemcitabine must be monitored closely. Laboratory facilities should be available to monitor patient status. Treatment for a patient compromised by toxicity may be required.

Prolongation of the infusion time and increased dosing frequency have been shown to increase toxicity.

Live attenuated and phenytoin This product is generally not recommended in combination with live attenuated vaccines and phenytoin.

Radiation therapy: See section 4.5.

Patients with hepatic and renal impairment: Gemcitabine may not be given to patients with moderate-to-severe hepatic impairment or severe renal impairment (see sections 4.2 and 4.8). Gemcitabine must be used with caution in patients with mild hepatic impairment and those with mild-to-moderate renal dysfunction, as there is insufficient information from clinical studies to allow any clear dosage recommendations for these patient groups. Administration of gemcitabine to patients with a history of liver metastases or hepatitis, alcoholism or liver cirrhosis may lead to exacerbation of the underlying hepatic dysfunction.

Based on the few data available, no constant significant effects on the pharmacokinetic properties of gemcitabine were observed in patients with mild-to-moderate renal dysfunction (glomerular filtration rate: 30-80 ml/min). A few cases of renal failure, including haemolytic-uraemic syndrome, have been reported. In patients with impaired renal function, gemcitabine should only be administered with caution (see section 4.8). Gemcitabine treatment should be discontinued at the first signs of micro- angiopathic haemolytic anaemia, and in cases of rapidly falling haemoglobin levels with concomitant thrombocytopenia, elevation of serum bilirubin, serum creatinine, urea or LDH. Renal failure may not be reversible, even with discontinuation of therapy, and dialysis may be required. Use of gemcitabine was associated with the reactivation of viral , potentially fatal. In patients at risk, prescription of gemcitabine should be preceded by a virological workup, in order to treat them if necessary.

Sequential use (> or = 4 weeks) of radiotherapy of the pancreatic area together with gemcitabine exposes the patient to a risk of hepatic necrosis.

Patients with compromised bone marrow function: In patients with impaired bone-marrow function, the treatment should be started with caution. As with other cytotoxic treatments, the risk of cumulative bone-marrow suppression must be considered when gemcitabine treatment is given together with other chemotherapy. Gemcitabine can suppress bone marrow function as manifested by leucopenia, thrombocytopenia, and anaemia. Suspension or modification of therapy should be considered when drug-induced marrow depression is detected. Guidelines regarding dose modifications are provided in section 4.2 above. Peripheral blood counts may continue to fall after the drug is stopped.

Respiratory disorders: Pulmonary effects, sometimes severe (such as pulmonary oedema, interstitial pneumonitis, or adult respiratory distress syndrome), have been reported rarely in association with gemcitabine therapy (see section 4.8). The aetiology of these effects is unknown. If severe pulmonary effects (pulmonary oedema, interstitial pneumonia or ARDS) develop, gemcitabine must be discontinued. Early use of supportive care measures may help ameliorate the condition. The risk of adverse pulmonary reaction appears to be higher in patients with lung cancer and lung metastases than with other tumour types, which should be taken into consideration when treating such patients.

Blood and : Prior to each dose, a platelet, leukocyte and granulocyte count must be performed (see section 4.2). Peripheral blood counts may continue to fall after discontinuation of gemcitabine treatment. If extravasation occurs, the infusion must be stopped immediately and started again in another blood vessel. The patient should be monitored carefully after the administration.

Vascular Disorders Due to the risk of cardiac and/or vascular disorder with gemcitabine, particular caution must be exercised with patients presenting a cardiovascular history. Gemcitabine will be used with caution in patients with Raynaud’s syndrome or scleroderma, due to an increased risk of peripheral arterial ischemia.

Microangiopathic haemolytic anaemia Gemcitabine should be discontinued at the first signs of any evidence of microangiopathic haemolytic anaemia such as rapidly falling haemoglobin with concomitant thrombocytopenia, elevation of serum bilirubin, serum creatinine, blood urea nitrogen, or LDH, which may indicate development of haemolytic uraemic syndrome (see section 4.8). Renal failure may not be reversible, even with discontinuation of therapy, and dialysis may be required.

Cutaneous disorders The risk of occurrence of inflammatory cutaneous reactions is increased in patients presenting lymphoedema, a history of irradiation or of deep venous thrombosis (see section 4.8).

Contraception Women of childbearing potential and men should use effective contraception during treatment (see section 4.6).

[For 200 mg strength:] This medicinal product contains less than 1 mmol sodium (23 mg) per vial, i.e. essentially 'sodium- free'.

[For 1 g strength:] This medicinal product contains less than 1 mmol sodium (23 mg) per vial, i.e. essentially 'sodium- free'.

4.5 Interaction with other medicinal products and other forms of interaction

Radiation therapy:

Concomitant radiation therapy (given together with gemcitabine or ≤ 7 days apart) The toxicity of such combined treatment is dependent on many different factors, including the gemcitabine dose and dosing frequency, the dose of radiation given, preparation for radiotherapy, irradiated tissue type and the volume of radiation given. In preclinical and clinical studies, gemcitabine has been shown to have radiosensitising activity.

In a single clinical study, where patients with non-small cell lung cancer were each given up to 1000 mg/m2 doses of gemcitabine for up to 6 consecutive weeks in conjunction with thoracic radiation, toxicity was observed in the form of severe and potentially life-threatening mucositis (especially oesophagitis and pneumonitis), particularly in patients receiving large volumes of radiotherapy (median treatment volumes = 4795 cm3). Subsequent studies have shown that it is feasible to administer gemcitabine at lower doses with concurrent radiotherapy with predictable toxicity. In a Phase II study, thoracic radiotherapy at 66Gy was performed concomitantly to the use of gemcitabine (600 mg/m2 four times) and cisplatin (80 mg/m2, twice) over a 6-week period.

However, the optimal dosing regimen for safe administration of gemcitabine together with therapeutic radiation doses has not yet been established.

Sequential (given > 7 days apart): Available information does not indicate any enhanced toxicity with administration of gemcitabine in patients who receive prior radiation, other than radiation recall. Data suggest that gemcitabine can be started after the acute effects of radiation have resolved or at least one week after radiation. Available information does not indicate any enhanced toxicity from radiation therapy following gemcitabine exposure.

Interactions common to all cytotoxics: Due to the increase of thrombotic risk in case of tumeral diseases, the use of anticoagulative treatment is frequent. The high intra-individual variability of the coagulability during diseases, and the eventuality of interaction between oral and anticancer chemotherapy require, if it is decided to treat the patient with oral anticoagulants, to increase frequency of the INR (International Normalised Ratio) monitoring.

Concomitant use contraindicated (see section 4.3): Yellow fever vaccine: risk of fatal generalised vaccinale disease.

Concomitant use not recommended: Live attenuated vaccines (except yellow fever): risk of systemic, possible fatal disease. This risk is increased in subjects who are already immunosuppressed by their underlying disease.Use an inactivated vaccine where this exists (poliomyelitis) Phenytoin: Risk of exacerbation of convulsions resulting from the decrease of phenytoin digestive absorption by cytotoxic drug or risk of toxicity enhancement or lose of efficacy of the cytotoxic drug due to increased hepatic by phenytoin.

Concomitant use to take into consideration: Ciclosporine,: Excessive with risk of lymphoproliferation.

4.6 Pregnancy and lactation

Pregnancy: There are no data on the use of gemcitabine in pregnant patients. Studies in animals have shown, reproductive toxicity (see section 5.3). During pregnancy, particularly during the first trimester, cytotoxic medicinal products should be given only when there is a compelling indication for their use and in cases where the potential benefits of treatment to the mother are deemed to outweigh the risks for the foetus. Thus, in oder to avoid pregnancy women of childbearing age and men have to use effective contraceptive measures during treatment and for 3 months after discontinuation of treatment. Men should be advised to seek further advice regarding cryoconservation of sperm prior to treatment because of the possibility of infertility.

Lactation: It is unknown if gemcitabine is excreted in human milk. Lactation is contra-indicated due to the potential harmful effects to the newborn. Weaning is required in cases where gemcitabine treatment during lactation is absolutely necessary.

Fertility: There are no human data on the effect of gemcitabine on fertility. In animals adverse effects of gemcitbaine have been observed (see section 5.3).

4.7 Effects on ability to drive and use machines

[XXX] has minor or moderate influence on the ability to drive and use machines. Therefore, even when used as directed, gemcitabine can affect alertness to such an extent that the ability to drive and use machines is impaired. This is particularly valid in combination with alcohol.

4.8 Undesirable effects

The following table gives an overview of adverse events based on clinical study reports and spontaneous post-marketing reports.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

The following undesirable effects have been divided into the following categories: Very common: ≥1/10 Common: ≥1/100 to <1/10 Uncommon: ≥1/1,000 to <1/100 Rare: ≥1/10,000 to <1/1,000 Very rare: <1/10,000, not known (cannot be estimated from the available data)

Cardiac disorders Very rare Myocardial infarction, congestive heart failure, arrhythmia (predominantly supraventricular).

Blood and lymphatic system disorders Very common Leukopenia, thrombocytopenia, anaemia, neutropenia (Grade 3 = 19.3%; Grade 4 = 6%) (see sections 4.2 and 4.4). Common Febrile neutropenia. Very rare Thrombocytosis.

Nervous system disorders Common Headache, somnolence, insomnia. Very rare Cerebro-vascular accident.

Respiratory, thoracic and mediastinal disorders Very common Dyspnoea. Common Cough, rhinitis. Uncommon Pulmonary oedema, bronchospasm (see section 4.3), interstitial pneumonitis (see section 4.4). Rare Adult respiratory distress syndrome (ARDS) (see section 4.4).

Gastrointestinal disorders Very common Nausea, vomiting. Common Mucositis, stomatitis, diarrhoea and constipation. Very rare Ischemic colitis.

Renal and urinary disorders Very common Mild proteinuria, haematuria. Rare Renal failure, haemolytic uraemic syndrome (see section 4.4).

Skin and subcutaneous tissue disorders Very common Cutaneous eruption, often accompanied by pruritus. Common Sweating, pruritus, alopecia. Rare Scalling, blister and sore formation. Very rare Severe skin reactions, including desquamation and bullous skin eruptions, including Lyell’s syndrome and Stevens-Johnson syndrome. Inflammatory cutaneous reactions, clinically suggesting infectious cellulitis or erysipelas (see section 4.4).

Musculoskeletal and connective tissue disorders Common Myalgia, back pain.

Metabolism and nutrition disorders Common Loss of appetite.

Injury, poisoning and procedural complications Frequency not known Radiation damage and “radiation recall” (see section 4.5) (cannot be determined on the basis of available data)

Vascular disorders Rare Hypotension. Very rare Clinical signs of peripheral vasculitis or gangrene.

General disorders and administration site conditions Very common Oedema/ peripheral oedema, influenza-like symptoms. The most common symptoms were: fever, headache, back pain, shivering, myalgia, asthenia, malaise and loss of appetite. Furthermore, there have been reports of coughing, rhinitis, tendency to sweating and insomnia. Common Fever, chills, asthenia and facial oedema. Rare Injection site reaction (mainly mild in nature).

Immune system disorders Very rare Anaphylactoid reactions.

Hepatobiliary disorders Very common Elevated transaminases (AST, ALT) and alkaline phosphatase. Common Elevated bilirubin. Rare Elevated gamma glutamyl transferase (GGT). Very rare: Serious hepatotoxicity, including liver failure and death (see sections 4.4).

Undesirable effects following combination therapy

“Gemcitabine plus paclitaxel: An increase was seen in the following Grade 3 and 4 events (gemcitabine + paclitaxel vs. paclitaxel alone) as follows: Haematological toxicity: haemoglobin (G3: 5.7% vs. 1.9%; G4: 1.1% vs. 0.4%); platelets (G3: 5.3% vs. 0%; G4: 0.4% vs 0%); neutrophils/granulocytes (G3: 31.3%vs. 4.2%; G4: 17.2% vs. 6.6%); febrile neutropenia (G3: 4.6% vs. 1.2%; G4: 0.4% vs. 0%). Non-haematological toxicity: fatigue (G3: 5.7% vs. 1.2%; G4: 0.8% vs. 0.4%); diarrhoea (G3: 3.1% vs. 1.9%; G4: 0% vs. 0%). The frequency of grade 3 and 4 haematological toxicities, particularly neutropenia, increases when gemcitabine is used in combination with paclitaxel. However, the increase in these adverse reactions is not associated with an increased incidence of or haemorrhagic events. Fatigue and febrile neutropenia occur more frequently when gemcitabine is used in combination with paclitaxel. Fatigue, which is not associated with anaemia, usually resolves after the first cycle.

Gemcitabine plus cisplatin: An increase was seen in the following Grade 3 and 4 events (gemcitabine + cisplatin v MVAC (, , , and cisplatin)) as follows: Haematological toxicity: haemoglobin (G3: 24% vs. 16%; G4: 4% vs. 2%); platelets (G3: 29% vs. 8%; G4: 29% vs. 13%). Non- haematological toxicity: nausea and vomiting (G3: 22% vs. 19%; G4 0% vs. 2%); diarrhoea (G3: 3% vs. 8%; G4: 0% vs. 1%); (G3: 2% vs. 10%; G4: 1% vs. 5%); stomatitis (G3: 1% vs. 18%; G4: 0% vs. 4%).

4.9 Overdose

There is no to gemcitabine. Single doses of up to 5.7g/m2 have been administered every fortnight as a 30-minute intravenous infusion with clinically acceptable toxicity. In the event of suspected overdose, the relevant blood counts of the patient should be monitored, and appropriate treatment initiated, if required.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: analogue, ATC code: L 01 BC O5

Cytotoxic activity in cell cultures: Gemcitabine exhibits significant cytotoxic activity against a variety of cultured murine and human tumour cells. It exhibits cell phase specificity,primarily killing cells undergoing DNA synthesis (S- phase) and under certain conditions blocking the progression of cells through the G1/S-phase boundary. In vitro, the cytotoxic action of gemcitabine is both concentration- and time-dependent.

Antitumour activity in preclinical models: In animal tumour models, the antitumour activity of gemcitabine is schedule dependent. Generally it was found that treatment at 3 or 4 day intervals was more effective and/or less toxic than daily administration of gemcitabine.

Cell metabolism and mechanism of action: Gemcitabine (dFdC) is metabolised intracellularly by kinases to the active diphosphate (dFdCDP) and triphosphate (dFdCTP) . The cytotoxic action of gemcitabine appears to be due to inhibition of DNA synthesis by two actions of dFdCDP and dFdCTP. First, dFdCDP inhibits reductase, which is uniquely responsible for catalysing the reactions that generate the deoxynucleoside triphosphates for DNA synthesis. Inhibition of this by dFdCDP causes a reduction in the concentrations of deoxynucleosides in general, and especially in that of dCTP. Second, dFdCTP competes with dCTP for incorporation into DNA (self-potentiation). Likewise, a small amount of gemcitabine may also be incorporated into RNA. Thus, the reduction in the intracellular concentration of dCTP potentiates the incorporation of dFdCTP into DNA. DNA polymerase epsilon is essentially unable to remove gemcitabine and repair the growing DNA strands. After gemcitabine is incorporated into DNA, one additional is added to the growing DNA strands. After this addition there is essentially a complete inhibition in further DNA synthesis (masked chain termination). After incorporation into DNA, gemcitabine then appears to induce the programmed cellular death process known as .

5.2 Pharmacokinetic properties

Pharmacokinetics of Gemcitabine:

The pharmacokinetics of gemcitabine has been examined in 353 patients in sevenstudies. The 121 women and 232 men raged in age from 29 and 79 years. Of these patients, approximately 45% had non-small cell lung cancer and 35% were diagnosed with pancreatic cancer. The following pharmacokinetic parameters were obtained for doses ranging from 500 to 2,592 mg/m2 that were infused from 0.4 to 1.2 hours.

Peak plasma concentration (obtained within 5 minutes of the end of the infusion): 3.2 to 45.5 μg/ml.

Volume of distribution of the central compartment: 12.4 l/m2 for women and 17.5 l/m2 for men (inter- individual variability was 91.9%).

Volume of distribution volume of the peripheral compartment: 47.4 l/m2. The volume of the peripheral compartment was not sensitive to gender.

Plasma-protein binding: Negligible.

Systemic clearance: Ranged from 29.2 l/hr/m2 to 92.2 l/hr/m2 depending on gender and age (inter- individual variability was 52.2%). Clearance for women is approximately 25% lower than the values for men. Although rapid, clearance for both men and women appears to decrease with age. For the recommended gemcitabine dose of 1,000 mg/m2 given as a 30 minute infusion, lower clearance values for women and men should not necessitate a decrease in the gemcitabine dose.

Half-life: Ranged from 42 to 94 minutes depending on age and gender. For the recommended dosing schedule, gemcitabine elimination should be virtually complete within 5 to 11 hours of the start of the infusion. Gemcitabine does not accumulate when administered once weekly.

Urinary excretion: less than 10% is excreted as unchanged drug.

Renal clearance: 2-7 l/h/m2.

Metabolism: Gemcitabine is rapidly metabolised by deaminase in the liver, kidneys, blood and other tissues. Intracellular metabolism of gemcitabine produces the gemcitabine mono-, di-, and triphosphates (dFdCMP, dFdCDP and dFdCTP), of which dFdCDP and dFdCTP are considered active. These intracellular metabolites have not been detected in plasma or urine. The primary metabolite, 2'-deoxy- 2',2'-difluorouridine (dFdU), is not active and is found in plasma and urine.

Pharmacokinetics of dFdCTP:

This metabolite is found in peripheral blood mononuclear cellsand the information below refers to these cells.

Terminal half-life: 0.7-12 hours.

Intracellular concentrations increase in proportion to gemcitabine doses of 35-350 mg/m2/30 min, which give steady-state concentrations of 0.4-5 µg/ml. At gemcitabine plasma concentrations above 5 µg/ml, dFdCTP llevels do not increase,suggesting that the formation is saturable in these cells.Parent plasma concentrations following a dose of 1,000 mg/m2/30 min are greater than 5 µg/ml for approximately 30 minutes after the end of the infusion, and greater than 0.4 μg/ml for an additional hour.

Pharmacokinetics of dFdU:

Peak plasma concentration (3-15 minutes after end of 30 minutes infusion, 1000 mg/m2): 28-52 μg/ml.

Trough concentration following once weekly dosing: 0.07-1.12 μg/ml with no apparent accumulation.

Triphasic plasma concentration versus time curve, mean half-life of terminal phase: 65 hours (33-84 hours).

Formation of dFdU from parent compound: 91-98%.

Mean volume of distribution of central compartme: 18 l/m2 (11-22l/m2).

2 2 Mean steady-state volume of distribution (VSS): 150 l/m (96-228 l/m ).

Tissue distribution: extensive.

Mean apparent clearance: 2.5 l/h/m2 (1-4 l/h/m2).

Urinary excretion: all.

Absolute elimination: Amount recoveredin one week: 92%-98%, of which 99% is dFdU; 1% of the dose is excreted in the faeces.

5.3 Preclinical safety data

In chronic toxicity studies of up to 6 months on mouse and canine models, the most significant finding was a change in haematopoiesis. Such changes were related to the cytotoxic properties of the substance and were reversible upon cessation of treatment. The effect was dependent on the dose and dosing frequency.

Long-term animal studies to evaluate the carcinogenic potential of gemcitabine have not been performed. Gemcitabine showed mutagenic potential in in vitro and in vivo tests. In reproductive studies several species teratogenic and fetotoxic effects (cleft palate, fused pulmonary artery, absence of gallbladder, decreased foetal viability) have been observed at doses below the human therapeutic dose. Furthermore, gemcitabine caused reversible hypospermatogenesis in male mice, which was dependent on the dose and dosing frequency. Whilst in animal studies, gemcitabine-induced changes in male fertility were identified, no changes in female fertility were observed.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

[For 200 mg strength:] Mannitol (E421) Sodium acetate trihydrate Sodium hydroxide (for pH-adjustment) Hydrochloric acid (for pH-adjustment)

[For 1 g strength:] Mannitol (E421) Sodium acetate trihydrate Sodium hydroxide (for pH-adjustment) Hydrochloride acid (for pH-adjustment)

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf life

As packaged for sale:

30 months.

After reconstitution: Chemical and physical in-use stability has been demonstrated for 24 hours at 30°C.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 30°C.

Reconstituted gemcitabine should not be refrigerated, as this results in crystallisation.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions. For storage conditions of the reconstituted medicinal product, see sections 6.3.

6.5 Nature and contents of the container

[XXX] 200 mg powder for solution for infusion 10 ml glass colourless type-I tubular glass vial with bromobutyl rubber stopper and with 20 mm crimp.

Pack size: 1 vial of 10 ml

[XXX] 1 g powder for solution for infusion. 50 ml glass vial colourless type-I moulded glass vial with bromobutyl rubber stopper and with 20 mm crimp.

Pack size: 1 vial of 50 ml.

6.6 Special precautions for disposal and other handling

Reconstituting the solution: Physiological saline solution without preservative agents is the only diluent approved for reconstituting gemcitabine solution for infusion. Although incompatibilities have not been observed, mixing gemcitabine with other substances during reconstitution or administration is not recommended. Following dilution, the upper gemcitabine concentration limit is 38 mg/ml. Dilution to concentrations above 38 mg/ml may result in incomplete dissolution and should be avoided.

To reconstitute the product, 5 ml (min.) or 25 ml (min.) of 0.9% physiological saline solution is added to the 200 mg vial or 1 g vial, respectively (both yielding a final concentration of 38 mg/ml and a displacements volume of 0.26 ml or 1.3 ml respectively). During reconstitution of the solution, the diluent should be added slowly down the side of the vial. Then, shake to dissolve. Further dilution with 0.9% physiological saline solution is possible.

After dilution, the solution for infusion should be inspected visually for particulate matter and discolouration. Only clear solutions practically free from suspended particles should be used.

Handling: Standard precautions for reconstituting cytotoxic agents must be observed. The preparation of injectable solutions of cytotoxic agents must be carried out by trained specialist personnel with knowledge of the medicines used, in conditions that guarantee the protection of the environment and, particular, the protection of personnel handling the medicines. It requires a preparation area reserved for this purpose. It is forbidden to smoke, eat or drink in this area.

Personnel must be provided with appropriate handling materials, notably long sleeved gowns, protection masks, caps, protective goggles, sterile single-use gloves, protective covers for the work area and collection bags for waste.

Cytotoxic preparations should not be handled by pregnant staff. If the product is allowed to come into contact with the eyes, severe irritation may result. In such an event, the eyes should be washed thoroughly and immediately. Consult a doctor if irritation persists. If the solution should come into contact with skin, rinse the affected area thoroughly with water. Excreta and vomit must be handled with care.

Disposal All items used for preparation, administration or otherwise coming into contact with gemcitabine should undergo disposal according to hospital standard procedures applicable to cytotoxic agents with due regard to current laws related to the disposal of hazardous waste.

Any unused product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

<[To be completed nationally]>

8 MARKETING AUTHORISATION NUMBER(S)

<[To be completed nationally]>

9 DATE OF FIRST AUTHORIZATION/RENEWAL OF AUTHORIZATION

<[To be completed nationally]>

10 DATE OF REVISION OF THE TEXT