GEMCITABINE

Gemcitabine should only be prescribed by a physician qualified in the use of anti- cancer chemotherapy. Recommended posology Bladder cancer Combination use The recommended dose for gemcitabine is 1000 mg/m², given by 30-minute infusion.

The dose should be given on Days 1, 8 and 15 of each 28-day 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 28-day cycle. This 4-week 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 cancer The recommended dose of gemcitabine is 1000 mg/m², given by 30-minute 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 cancer Monotherapy The recommended dose of gemcitabine is 1000 mg/m², given by 30-minute intravenous infusion. This should be repeated once weekly for 3 weeks, followed by a 1-week rest period. This 4-week 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 use The recommended dose for gemcitabine is 1250 mg/m² body surface area given as a 30-minute intravenous infusion on Day 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. 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 cancer Combination use Gemcitabine in combination with carboplatin is recommended using gemcitabine 1000 mg/m² administered on Days 1 and 8 of each 21-day cycle as a 30-minute intravenous infusion.

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 toxicity Dose modification due to non haematological toxicity Periodic 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 toxicity Initiation of a cycle For 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 cycle Dose 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 cisplatin Absolute granulocyte count (x 106/l) Platelet count (x 106/l) Percentage of standard dose of Gemcitabine 38 mg/ml powder for solution for infusion (%) > 1,000 and > 100,000 100 500-1,000 or 50,000-100,000 75 <500 or < 50,000 Omit dose * *Treatment omitted will not be re-instated 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 paclitaxel Absolute granulocyte count (x 106/l) Platelet count (x 106/l) Percentage of standard dose of Gemcitabine 38 mg/ml powder for solution for infusion(%) ≥ 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 Omit dose* *Treatment omitted will not be re-instated 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 carboplatin Absolute granulocyte count (x 106/l) Platelet count (x 106/l) Percentage of standard dose of Gemcitabine 38 mg/ml powder for solution for infusion (%) > 1,500 and ≥ 100,000 100 1000-1,500 or 75,000-100,000 50 <1000 or < 75,000 Omit dose * *Treatment omitted will not be re-instated 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 indications The gemcitabine dose should be reduced to 75% of the original cycle initiation dose, in the case of the following […]

The most commonly reported adverse drug reactions associated with gemcitabine 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% patients; dyspnoea reported in 10-40% 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.

4). 2).

Clinical trial data Frequencies 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), Not Known (cannot be estimated from the available data)... 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. 3 %; Grade 4 = 6 %). 4) Gastrointestinal disorders Very common • Vomiting • Nausea Common • Diarrhoea • Stomatitis and ulceration of the mouth • Constipation Very Rare • Ischaemic colitis Hepatobiliary disorders Very common • Elevation of liver transaminases (AST and ALT) and alkaline phosphatase Common • Increased bilirubin Uncommon • Serious hepatotoxicity, including liver failure and death Rare • Increased gamma-glutamyl transferase (GGT) Skin and subcutaneous tissue disorders Very common • Allergic skin rash frequently associated with pruritus • Alopecia Common • Itching • Sweating Rare • Severe skin reactions, including desquamation and bullous skin eruptions • Ulceration • Vesicle and sore formation • Scaling Very rare • Toxic epidermal necrolysis • Stevens-Johnson Syndrome Not known • Pseudocellulitis • Acute generalised exanthematous pustulosis.

4) General disorders and administration site conditions Very common • Influenza-like symptoms - the most common symptoms are fever, headache, chills, myalgia, asthenia and anorexia. Cough, rhinitis, malaise, perspiration and sleeping difficulties have also been reported.

• Oedema/peripheral oedema including facial oedema. 5). • Radiation recall Combination use in breast cancer The frequency of grade 3 and 4 haematological toxicities, particularly neutropaenia, 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 neutropaenia occur more frequently when gemcitabine is used in combination with paclitaxel.

Fatigue, which is not associated with anaemia, usually resolves after the first cycle. 0% of patients in the paclitaxel arm. Combination use in bladder cancer Grade 3 and 4 Adverse Events MVAC versus Gemcitabine plus cisplatin Number (%) of Patients MVAC (methotrexate, vinblastine, doxorubicin and cisplatin) arm (N=196) Gemcitabine plus cisplatin arm (N=200) Grade 3 Grade 4 Grade 3 Grade 4 Laboratory Anaemia 30 (16) 4 (2) 47 (24) 7 (4) Thrombocytopaenia 15 (8) 25 (13) 57 (29) 57 (29) Non-laboratory Nausea and vomiting 37 (19) 3 (2) 44 (22) 0 (0) Diarrhoea 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) Combination use […]

Prolongation of the infusion time and increased dosing frequency have been shown to increase toxicity. Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP), which can be life-threatening or fatal, have been reported in association with gemcitabine treatment.

Patients should be advised of the signs and symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of these reactions appear, gemcitabine should be withdrawn immediately. Haematological toxicity Gemcitabine can suppress bone marrow function as manifested by leucopaenia, thrombocytopenia and anaemia.

Patients receiving gemcitabine should be monitored prior to each dose for platelet, leucocyte and granulocyte counts. 2). 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.

2). Administration 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 impairment. Laboratory evaluation of renal and hepatic function (including virological tests) should be performed periodically.

5 for details and recommendations for use). 5). Posterior reversible encephalopathy syndrome Reports of posterior reversible encephalopathy syndrome (PRES) with potentially severe consequences have been reported in patients receiving gemcitabine as single agent or in combination with other chemotherapeutic agents.

Acute hypertension and seizure activity were reported in most gemcitabine patients experiencing PRES, but other symptoms such as headache, lethargy, confusion and blindness could also be present. Diagnosis is optimally confirmed by magnetic resonance imaging (MRI).

PRES was typically reversible with appropriate supportive measures. Gemcitabine should be permanently discontinued and supportive measures implemented, including blood pressure control and anti-seizure therapy, if PRES develops during therapy.

Cardiovascular Due to the risk of cardiac and/or vascular disorders with gemcitabine, particular caution must be exercised with patients presenting a history of cardiovascular events. 8). The condition is usually treatable if recognised early and managed appropriately, but fatal cases have been reported.

The condition involves systemic capillary hyperpermeability during which fluid and proteins from the intravascular space leak into the interstitium. The clinical features include generalised oedema, weight gain, hypoalbuminaemia, severe hypotension, acute renal impairment and pulmonary oedema.

Gemcitabine should be discontinued and supportive measures implemented if capillary leak syndrome develops during therapy. Capillary leak syndrome can occur in later cycles and has been associated in the literature with adult respiratory distress syndrome.

Pulmonary Pulmonary effects, sometimes severe (such as pulmonary oedema, interstitial pneumonitis or adult respiratory distress syndrome (ARDS)) have been reported in association with gemcitabine therapy. If such effects develop, consideration should be made to discontinuing gemcitabine therapy.

Early use of supportive care measure may help ameliorate the condition. 8). HUS is a potentially life-threatening disorder. Gemcitabine should be discontinued at the first signs of any evidence of microangiopathic haemolytic anaemia, such as rapidly falling haemoglobin with concomitant thrombocytopaenia, 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. 3). 6). Sodium The 200 mg vial contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially ‘sodium-free’. The 1000 mg vial contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially ‘sodium-free’.

75% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

1. 6).