Drug Description
One vial contains gemcitabine hydrochloride equivalent to 200 mg gemcitabine.One vial contains gemcitabine hydrochloride equivalent to 1,000 mg gemcitabine.After reconstitution, the solution contains 38 mg/ml of gemcitabine. Excipients:Each 200 mg vial contains 3.5 mg (<1 mmol) sodium.Each 1,000 mg vial contains 17.5 mg (<1 mmol) sodium.

Presentation
Powder for solution for infusion. White to off-white plug or powder.

Indications
Gemcitabine is indicated for the treatment of locally advanced or metastatic bladder cancer in combination with cisplatin.Gemcitabine is indicated for treatment of patients with locally advanced or metastatic adenocarcinoma of the pancreas.Gemcitabine, in combination with cisplatin, is indicated as first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). Gemcitabine monotherapy can be considered in elderly patients or those with performance status 2.Gemcitabine is indicated for the treatment of patients with locally advanced or metastatic epithelial ovarian carcinoma, in combination with carboplatin, in patients with relapsed disease following a recurrence-free interval of at least 6 months after platinum-based, first-line therapy.Gemcitabine, in combination with paclitaxel, is indicated for the treatment of patients with unresectable, locally recurrent or metastatic breast cancer who have relapsed following adjuvant/neoadjuvant chemotherapy. Prior chemotherapy should have included an anthracycline unless clinically contraindicated.

Adult Dosage
Gemcitabine should only be prescribed by a physician qualified in the use of anti-cancer chemotherapy.Recommended posology:Bladder cancerCombination useThe recommended dose for gemcitabine is 1,000 mg/m2, given by 30minute infusion. The dose should be given on Days 1, 8 and 15 of each 28day cycle in combination with cisplatin. Cisplatin is given at a recommended dose of 70 mg/m2 on Day 1 following gemcitabine or Day 2 of each 28day cycle. This 4week cycle is then repeated. Dosage reduction with each cycle or within a cycle may be applied based upon the grade of toxicity experienced by the patient.Pancreatic cancerThe recommended dose of gemcitabine is 1,000 mg/m2, given by 30minute intravenous infusion. This should be repeated once weekly for up to 7 weeks followed by a week of rest. Subsequent cycles should consist of injections once weekly for 3 consecutive weeks out of every 4 weeks. Dosage reduction with each cycle or within a cycle may be applied based upon the grade of toxicity experienced by the patient.Non-small cell lung cancerMonotherapyThe recommended dose of gemcitabine is 1,000 mg/m2, given by 30minute intravenous infusion. This should be repeated once weekly for 3 weeks, followed by a 1week rest period. This 4week cycle is then repeated. Dosage reduction with each cycle or within a cycle may be applied based upon the grade of toxicity experienced by the patient.Combination useThe recommended dose for gemcitabine is 1,250 mg/m2 body surface area given as a 30minute intravenous infusion on Days 1 and 8 of the treatment cycle (21 days). Dosage reduction with each cycle or within a cycle may be applied based upon the grade of toxicity experienced by the patient.Cisplatin has been used at doses between 75-100 mg/m2 once every 3 weeks.Breast cancerCombination useGemcitabine, in combination with paclitaxel, is recommended using paclitaxel (175 mg/m2) administered on Day 1 over approximately 3hours as an intravenous infusion, followed by gemcitabine (1,250 mg/m2) as a 30minute intravenous infusion on Days 1 and 8 of each 21day cycle. Dose reduction with each cycle or within a cycle may be applied based upon the grade of toxicity experienced by the patient. Patients should have an absolute granulocyte count of at least 1,500 (x 106/l) prior to initiation of gemcitabine + paclitaxel combination.Ovarian cancerCombination useGemcitabine, in combination with carboplatin, is recommended using gemcitabine 1,000 mg/m2 administered on Days 1 and 8 of each 21day cycle as a 30minute intravenous infusion. After gemcitabine, carboplatin will be given on Day 1 consistent with a target area under curve (AUC) of 4.0 mg/ml•min. Dosage reduction with each cycle or within a cycle may be applied based upon the grade of toxicity experienced by the patient.Monitoring for toxicity and dose modification due to toxicityDose modification due to non-haematological toxicityPeriodic physical examination and checks of renal and hepatic function should be made to detect non-haematological toxicity. Dosage reduction with each cycle or within a cycle may be applied based upon the grade of toxicity experienced by the patient. In general, for severe (Grade 3 or 4) non-haematological toxicity, except nausea/vomiting, therapy with gemcitabine should be withheld or decreased depending on the judgement of the treating physician. Doses should be withheld until toxicity has resolved, in the opinion of the physician.For cisplatin, carboplatin, and paclitaxel dosage adjustment in combination therapy, please refer to the corresponding Summary of Product Characteristics.Dose modification due to haematological toxicityInitiation of a cycleFor all indications, the patient must be monitored before each dose for platelet and granulocyte counts. Patients should have an absolute granulocyte count of at least 1,500 (x 106/l) and platelet count of 100,000 (x 106/l) prior to the initiation of a cycle.Within a cycleDose modifications of gemcitabine within a cycle should be performed according to the following tables:Dose modification of gemcitabine within a cycle for bladder cancer, NSCLC and pancreatic cancer, given in monotherapy or in combination with cisplatinAbsolute granulocyte count(x 106 /l)Platelet count(x 106 /l)Percentage of standard dose of GEMZAR (%)> 1,000 and> 100,000100500-1,000 or50,000 - 100,00075< 500 or<50,000Omit dose**Treatment omitted will not be reinstated within a cycle before the absolute granulocyte count reaches at least 500 (x106/l) and the platelet count reaches 50,000 (x106/l).Dose modification of gemcitabine within a cycle for breast cancer, given in combination with paclitaxelAbsolute granulocyte count(x 106 /l)Platelet count(x 106 /l)Percentage of standard dose of GEMZAR (%)≥1,200 and>75,0001001,000-< 1,200 or50,000-75,00075700-<1,000≥50,00050< 700 or< 50,000Omit dose**Treatment omitted will not be reinstated within a cycle. Treatment will start on Day 1 of the next cycle once the absolute granulocyte count reaches at least 1,500 (x106/l) and the platelet count reaches 100,000 (x106/l).Dose modification of gemcitabine within a cycle for ovarian cancer, given in combination with carboplatinAbsolute granulocyte count(x 106 /l)Platelet count(x 106 /l)Percentage of standard dose of GEMZAR (%)> 1,500 and≥ 100,0001001,000-1,500or75,000 - 100,00050< 1,000 or< 75,000Omit dose**Treatment omitted will not be reinstated within a cycle. Treatment will start on Day 1 of the next cycle once the absolute granulocyte count reaches at least 1,500 (x106/l) and the platelet count reaches 100,000 (x106/l).Dose modifications due to haematological toxicity in subsequent cycles, for all indicationsThe gemcitabine dose should be reduced to 75% of the original cycle initiation dose, in the case of the following haematological toxicities:Absolute granulocyte count < 500 x 106/l for more than 5 days Absolute granulocyte count < 100 x 106/l for more than 3 daysFebrile neutropenia Platelets < 25,000 x 106/lCycle delay of more than 1 week due to toxicity Method of administrationGEMZAR is tolerated well during infusion and may be administered ambulant. If extravasation occurs, generally the infusion must be stopped immediately and started again in another blood vessel. The patient should be monitored carefully after the administration.Special populationsPatients with renal or hepatic impairmentGemcitabine should be used with caution in patients with hepatic or renal insufficiency as there is insufficient information from clinical studies to allow for clear dose recommendations for these patient populations.Elderly population (> 65 years)Gemcitabine has been well tolerated in patients over the age of 65. There is no evidence to suggest that dose adjustments, other than those already recommended for all patients, are necessary in the elderly.Paediatric population (< 18 years)Gemcitabine is not recommended for use in children under 18 years of age due to insufficient data on safety and efficacy.

Contra Indications
Hypersensitivity to the active substance or to any of the excipients.Breast-feeding

Special Precautions
Prolongation of the infusion time and increased dosing frequency have been shown to increase toxicity.Haematological toxicityGemcitabine can suppress bone marrow function as manifested by leucopenia, thrombocytopenia and anaemia.Patients receiving gemcitabine should be monitored prior to each dose for platelet, leucocyte and granulocyte counts. Suspension or modification of therapy should be considered when drug-induced bone marrow depression is detected. However, myelosuppression is short-lived and usually does not result in dose reduction and rarely in discontinuation.Peripheral blood counts may continue to deteriorate after gemcitabine administration has been stopped. 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.Hepatic insufficiencyAdministration of gemcitabine in patients with concurrent liver metastases or a pre-existing medical history of hepatitis, alcoholism or liver cirrhosis may lead to exacerbation of the underlying hepatic insufficiency.Laboratory eva luation of renal and hepatic function (including virological tests) should be performed periodically.Gemcitabine should be used with caution in patients with hepatic insufficiency or with impaired renal function as there is insufficient information from clinical studies to allow clear dose recommendation for this patient population.Concomitant radiotherapyConcomitant radiotherapy (given together or 7 days apart): Toxicity has been reported.Live vaccinationsYellow fever vaccine and other live attenuated vaccines are not recommended in patients treated with gemcitabine.CardiovascularDue to the risk of cardiac and/or vascular disorders with gemcitabine, particular caution must be exercised with patients presenting a history of cardiovascular events.PulmonaryPulmonary effects, sometimes severe (such as pulmonary oedema, interstitial pneumonitis or adult respiratory distress syndrome (ARDS)) have been reported in association with gemcitabine therapy. The aetiology of these effects is unknown. If such effects develop, consideration should be made to discontinuing gemcitabine therapy. Early use of supportive care measure may help ameliorate the condition.RenalClinical findings consistent with the haemolytic uraemic syndrome (HUS) were rarely reported in patients receiving gemcitabine. 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. Renal failure may not be reversible with discontinuation of therapy and dialysis may be required.FertilityIn fertility studies, gemcitabine caused hypospermatogenesis in male mice. Therefore, men being treated with gemcitabine are advised not to father a child during and up to 6 months after treatment and to seek further advice regarding cryoconservation of sperm prior to treatment because of the possibility of infertility due to therapy with gemcitabine.SodiumGEMZAR 200 mg contains 3.5 mg (<1 mmol) sodium per vial. This should be taken into consideration by patients on a controlled sodium diet.GEMZAR 1000 mg contains 17.5 mg (<1 mmol) sodium per vial. This should be taken into consideration by patients on a controlled sodium diet

Interactions
No specific interaction studies have been performed.RadiotherapyConcurrent (given together or 7 days apart) - Toxicity associated with this multimodality therapy is dependent on many different factors, including dose of gemcitabine, frequency of gemcitabine administration, dose of radiation, radiotherapy planning technique, the target tissue, and target volume. Pre-clinical and clinical studies have shown that gemcitabine has radiosensitising activity. In a single trial, where gemcitabine at a dose of 1,000 mg/m2 was administered concurrently for up to 6 consecutive weeks with therapeutic thoracic radiation to patients with non-small cell lung cancer, significant toxicity in the form of severe, and potentially life-threatening mucositis, especially oesophagitis, and pneumonitis was observed, particularly in patients receiving large volumes of radiotherapy [median treatment volumes 4,795 cm3]. Studies done subsequently have suggested that it is feasible to administer gemcitabine at lower doses with concurrent radiotherapy with predictable toxicity, such as a phase II study in non-small cell lung cancer, where thoracic radiation doses of 66 Gy were applied concomitantly with an administration with gemcitabine (600 mg/m2, four times) and cisplatin (80 mg/m2, twice) during 6 weeks. The optimum regimen for safe administration of gemcitabine with therapeutic doses of radiation has not yet been determined in all tumour types.Non-concurrent (given>7 days apart) - Analysis of the data does not indicate any enhanced toxicity when gemcitabine is administered more than 7 days before or after 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.Radiation injury has been reported on targeted tissues (e.g., oesophagitis, colitis, and pneumonitis) in association with both concurrent and non-concurrent use of gemcitabine.OthersYellow fever and other live attenuated vaccines are not recommended due to the risk of systemic, possibly fatal, disease, particularly in immunosuppressed patients.

Adverse Reactions
The most commonly reported adverse drug reactions associated with GEMZAR treatment include: nausea with or without vomiting, raised liver transaminases (AST/ALT) and alkaline phosphatase, reported in approximately 60% of patients; proteinuria and haematuria reported in approximately 50% of patients; dyspnoea reported in 1040% of patients (highest incidence in lung cancer patients); allergic skin rashes occur in approximately 25% of patients and are associated with itching in 10% of patients.The frequency and severity of the adverse reactions are affected by the dose, infusion rate and intervals between doses. Doselimiting adverse reactions are reductions in thrombocyte, leucocyte and granulocyte counts.Clinical trial dataFrequencies are defined as: 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).The following table of undesirable effects and frequencies is based on data from clinical trials. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.System Organ ClassFrequency groupingBlood and lymphatic system disordersVery Common •Leucopenia (Neutropenia Grade 3 = 19.3 %; Grade 4 = 6 %). Bone-marrow suppression is usually mild to moderate and mostly affects the granulocyte count.• Thrombocytopenia• Anaemia Common • Febrile neutropenia Very Rare• ThrombocytosisImmune system disordersVery Rare • Anaphylactoid reactionMetabolism and nutrition disordersCommon • AnorexiaPost-marketing experience (spontaneous reports): frequency not known (cannot be estimated from the available data) Nervous system disorders Cerebrovascular accident Cardiac disorders Arrythmias, predominantly supraventricular in nature Heart failure Vascular disorders Clinical signs of peripheral vasculitis and gangrene Respiratory, thoracic and mediastinal disorders Pulmonary oedema Adult respiratory distress syndrome Gastro-intestinal disorders Ischaemic coliti Hepato-biliary disorders Serious hepatotoxicity, including liver failure and death Skin and subcutaneous tissue disorders Severe skin reactions, including desquamation and bullous skin eruptions, Lyell's syndrome, Stevens-Johnson syndrome Renal and urinary disorders Renal failure Haemolytic uraemic syndrome Injury, poisoning and procedural complications Radiation recall Combination use in breast cancerThe 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 infections 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.Grade 3 and 4 Adverse Events Paclitaxel versus Gemcitabine plus paclitaxelNumber (%) of PatientsPaclitaxel arm (N=259)strong>Gemcitabine plus paclitaxel arm (N=262)Grade 3Grade 4Grade 3Grade 4LaboratoryAnaemia5 (1.9)1 (0.4)15 (5.7)3 (1.1)Thrombocytopenia0014 (5.3)1 (0.4)Neutropenia11 (4.2)17 (6.6)*82 (31.3)45 (17.2)*Non-laboratoryFebrile neutropenia3 (1.2)012 (4.6)1(0.4)Fatigue3 (1.2)1 (0.4)15 (5.7)2 (0.8)Diarrhoea5 (1.9)08 (3.1)0Motor neuropathy2(0.8)06(2.3)1(0.4)Sensory neuropathy9(3.5)014(5.3)1(0.4)*Grade 4 neutropenia lasting for more than 7 days occurred in 12.6% of patients in the combination arm and 5.0% of patients in the paclitaxel arm. Combination use in bladder cancerGrade 3 and 4 Adverse Events MVAC versus Gemcitabine plus cisplatinNumber (%) of PatientsMVAC (methotrexate, vinblastine, doxorubicin and cisplatin) arm (N=196)Gemcitabine plus cisplatin arm (N=200)Grade 3Grade 4Grade 3Grade 4LaboratoryAnaemia30(16)4(2)7(24)7(4)Thrombocytopenia15(8)25(13)57(29)57(29)Non-laboratoryNausea and vomiting37(19)3(2)44(22)0(0)Diarrhoea15(8)1(1)6(3)0(0)Infection19(10)10(5)4(2)1(1)Stomatitis34(18)8(4)2(1)0(0)Combination use in ovarian cancerGrade 3 and 4 Adverse Events Carboplatin versus Gemcitabine plus carboplatin Number (%) of PatientsCarboplatin arm (N=174)Gemcitabine plus carboplatin arm (N=175)Grade 3Grade 4Grade 3Grade 4LaboratoryAnaemia10(5.7)4(2.3)39(22.3)9(5.1)Neutropenia19(10.9)2(1.1)73(41.7)50(28.6)Thrombocytopenia18(10.3)2(1.1)53(30.3)8(4.6)Leucopenia11(6.3)1(0.6)84(48.0)9(5.1)Non-laboratoryHaemorrhage0(0.0)0(0.0)3(1.8)(0.0)Febrile neutropenia0(0.0)0(0.0)2(1.1)(0.0)Infection without neutropenia0(0)0(0.0)(0.0)1(0.6)Sensory neuropathy was also more frequent in the combination arm than with single-agent carboplatin.

Owner
Eli Lilly and Company Limited

Drug Availability
POM- Prescription only Medicine

Updated
26 May 2010