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 gemcitabine (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 cisplatin. Breast cancer: Treatment of locally advanced or metastatic breast cancer in combination with paclitaxel in patients experiencing a relapse after (neo)adjuvant chemotherapy. Prior chemotherapy should have included an anthracycline, 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 bone 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 platelet, 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 blood 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 antibiotic. • platelets <25 x 109/l • > 1-week postponement of subsequent treatment cycle due to toxicity. Table 3: Dose levels for gemcitabine and carboplatin 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 vaccine (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 drug toxicity may be required. Prolongation of the infusion time and increased dosing frequency have been shown to increase toxicity. Live attenuated vaccines 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).