GEMCITABINE

Gemcitabine can only be prescribed by a physician qualified in the use of anti-cancer therapy. Recommended posology Bladder cancer Combination use The recommended dose for gemcitabine is 1000 mg/m2, as a 30-minute infusion. The dose must be administered on Days 1, 8 and 15 for a 28-day cycle in combination with cisplatin.

Cisplatin is given at the recommended dose of 70 mg/m2 on Day 1 following gemcitabine or D2 of each 28-day cycle. This 4four-week cycle is then repeated. Dosage reduction with each cycle or within a cycle may be considered based upon the grade of toxicity experienced by the patient.

Pancreatic cancer The recommended dose is 1000 mg/m2, admistered as a 30-minute intravenous infusion. The administration should be repeated once weekly for 7 consecutive weeks followed by one week of rest. From the next cycle, the administration must be repeated once weekly for 3 consecutive weeks every 4 weeks.

Dosage reduction with each cycle or within a cycle may be considered based upon the grade of toxicity experienced by the patient. Non small Cell lung cancer Monotherapy The recommended dose is 1000 mg/m2, administered as a 30-minute intravenous infusion.

The administration should be repeated once weekly for 3 weeks, followed by a one-week rest period. This 4four-week cycle is then repeated. Dosage reduction with each cycle or within a cycle may be considered based upon the grade of toxicity experienced by the patient.

Combination use The recommended dose of gemcitabine is 1250 mg/m2 body surface area given as a 30-minute intravenous infusion on Days 1 and 8 of the treatment cycle (21 day cycles). Dosage reduction with each cycle or within a cycle may be considered 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 cancer Combination use To use gemcitabine in combination with paclitaxel is recommended to administer paclitaxel (175 mg/m2) on Day 1 over approximately 3-hours as an intravenous infusion, followed by gemcitabine (1250 mg/m2) as a 30-minute intravenous infusion on Days 1 and 8 of each 21-day cycle.

Dosage reduction with each cycle or within a cycle may be considered 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 in combination with paclitaxel .

Ovarian cancer Combination use The recommended dose of gemcitabine in combination with carboplatin is 1000 mg/m2 as a 30-minute intravenous infusion. On days 1 and 8 of each 21-day cycle. 0 mg/mL·min to be reached. Dosage reduction with each cycle or within a cycle may be considered based upon the grade of toxicity experienced by the patient.

Toxicity monitoring and dose modification due to toxicity Dose modification due to non haematological toxicity Periodic physical examination and checks of renal and hepatic function mustbe made to detect non- haematological toxicity.

Dosage reduction with each cycle or within a cycle may be considered based upon the grade of toxicity experienced by the patient. In general, in the event of severe (Grade 3 or 4) non-haematological toxicity, excluding nausea/vomiting, treatment with gemcitabine must be reduced or suspended in line with the judgement of the physician.

Treatment may be postponed, in-line with the judgement of the physician, until the toxicity has resolved. 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 undergo hematological monitoring before each dose; Complete Blood count with Differential and platelet.. Prior to the initiation of a cycle, patients must have an absolute granulocyte count of at least 1500 (x 106/L) and a platelet count of 100,000 (x 106/L).

Within a cycle Dose modifications of gemcitabine within a cycle must be adjusted as shown in the tables below: Dose modification of gemcitabine administed as a monotherapy or in combination with cisplatin within a cycle in bladder cancer, NSCLC and pancreatic cancer, Absolute granulocyte count (x 106/L) Platelet count (x 106/L) Percentage of the average dose of Gemcitabine (%) > 1000 and > 100,000 100 500-1000 or 50,000-100,000 75 <500 or < 50,000 No dose * * Omitted treatment is not to 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 in combination with paclitaxel within a cycle in breast cancer Absolute granulocyte count (x 106/L) Platelet count (x 106/L) Percentage of the average dose of Gemcitabine (%) ≥ 1200 and >75,000 100 1000- <1200 or 50,000-75,000 75 700- <1000 and ≥ 50,000 50 <700 or <50,000 Omit dose* *Omitted treatment is not to be re-instated within a cycle.

Treatment will start on day 1 of the next cycle once the absolute granulocyte count has reached at least 1,500 (x106/L) and the platelet count reaches 100,000 (x106/L). Dose modification of gemcitabine in combination with carboplatin within a cycle in breast cancer Absolute granulocyte count (x 106/L) Platelet count (x 106/L) Percentage of the average dose of Gemcitabine (%) > 1,500 and ≥ 100,000 100 1,000-1,500 or 75,000-100,000 50 <1,000 or < 75,000 Omit dose* *Omitted treatment isnot to be re-instated within a cycle.

Treatment will begin on day 1 of the next cycle once the absolute granulocyte count reaches at least 1,500 (x106/L) and the platelet count has reached 100,000 (x106/L). Dose modifications, in the following cycles, due to haematological toxicity cycles, for all indications The dose of gemcitabine must be reduced to 75% of the initial dose of the first cycle, in the event that the following […]

The most commonly reported adverse reactions associated with Gemcitabine include: nausea with or without vomiting, elevated liver transaminases (AST/ALT) and alkaline phosphatase levels, reported in approximately 60% of patients; proteinuria and haematuria reported in approximately 50% of patients; dyspnoea reported in 10 to 40% of patients (higher incidence rate in patients with lung cancer); allergic drug eruptions, occurring in approximately 25% of patients and are associated with pruritusin 10% of patients.

4). 2).

Data from clinical studiesFrequencies are defined as follows:

Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very Rare (<1/10,000) and frequency not known (cannot be estimated based on available data). The table below displaying the adverse reactions and their frequency is based on data from clinical studies.

Within each frequency grouping, adverse reactionsare presented in order of decreasing seriousness. System Organ Class Frequency grouping Infections and infestations Common • Infections. Unknown frequency • Sepsis. 3 %; Grade 4 = 6 %).

4) • Bronchospasm –usually mild and transient but may require parenteral treatment Rare • Pulmonary Oedema. 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 levels Common • Elevated bilirubin Uncommon • Serious hepatotoxicity, including hepatic failure and death.

Rare • Elevated gamma-glutamyl transferase (GGT) levels Skin and subcutaneous tissue disorders Very common • Allergic skin rash frequently associated with pruritus • Alopecia Common • Pruritus • Sweating Rare • Ulceration • Blister and sore formation • ScalingDesquamation • Severe skin reactions, including desquamation and bullous eruptions Very rare • Toxic epidermal necrolysis • Stevens-Johnson syndrome Not known • Pseudocellulitis.

• Acute generalized exanthematous pustulosis. 4). 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 oedemaincluding facial oedema. 5). 4) Injury, poisoning and procedural complications Radiation recall Combination use in breast cancer The frequency of grade 3 and 4 haematological toxicity, including neutropenia, increases when gemcitabine is administeredin combination with paclitaxel.

However, the increased frequency of these adverse reactions is not associated with an increased rate of infectiousor haemorrhagic events. Fatigue and febrile neutropaenia occur more frequently when gemcitabine is adminstered in combination with paclitaxel.

Fatigue, not associated with anaemia, generally resolves after the first cycle. Grade 3 and 4 Adverse Reactions Paclitaxel versus gemcitabine plus paclitaxel Number (%) of Patients Paclitaxel arm (N=259) Gemcitabine plus Paclitaxel arm (N=262) Grade 3 […]

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, manifesting as leucopaenia, thrombocytopaenia and anaemia.

Patients receiving gemcitabine should be monitored prior to each dose, including for platelet, leukocyte and granulocyte counts. 2). However, myelosuppression is short lived and usually does not require a dose reduction and only rarely requires discontinuation.

Blood counts may continue to decrease after cessation of treatment with gemcitabine. The treatment must be initiated with caution in patients with impaired bone marrow function, As with other cytolytic treatments, the risk of cumulative bone-marrow suppression taken into consideration in cases of combined or sequential chemotherapy.

2). The administration of gemcitabine in patients who also have liver metastases or a history of hepatitis, alcoholism or cirrhosis may results in exacerbation of underlying hepatic impairment. Renal and hepatic function must be checked periodically (including virology testing).

5 for details and recommendations for use). 5). Cardiovascular Due to the risk of cardiac and/or vascular disorders ongemcitabine, special attention must be paid topatients with a history of cardiovascular events. 8). In general, treatments for this condition exist if it is diagnosed early and treated appropriately, but fatal cases have been reported.

Thiscondition involves causes systemic capillary hyperpermeability, with leakage of fluid and proteins from the intravascular space into the interstitium. The clinical characterstics include generalised oedema, weight gain, hypoalbuminaemia, severe hypotension, acute renal failure and pulmonary oedema.

Gemcitabine must be stopped and symptomatic treatments must be initiated if capillary leak syndrome occurs during treatment. Capillary leak syndrome may occur during subsequent cycles and has been associated with adult respiratory distress syndrome in the literature.

Posterior reversible encephalopathy syndrome () Cases of posterior reversible encephalopathy syndrome (PRES) with potentially severe consequences have been reported in patients receiving gemcitabine alone or in combination with other chemotherapeutic anti-cancer agents.

Severe hypertension and seizures have been reported in the majority of patients receiving gemcitabine who experiencedPRES, but other symptoms, such as headaches. Lethargy, confusion and blindness may also be present. The diagnosis is ideally confirmed through magnetic resonance imaging (MRI).

PRES was generally reversible with appropriate symptomatic treatment. If PRES develops during treatment,. gemcitabine mustbe permanently discontinued and symptomatic treatments must be initiated such as blood pressure control and anti-seizure medication.

Pulmonary Pulmonary effects, which are sometimes severe (such as pulmonary oedema, interstitial lung disease and adult respiratory distress syndrome (ARDS)) have been reported in association with gemcitabine treatment. If such effects occur, discontinuation of treatment with gemcitabine should be considered.

Early initiation of supportive measures may help to improve the patient’s condition. 8). HUS is a potentially life-threatening condition. Gemcitabine must be stopped at the first signs of microangiopathic haemolytic anaemia, such as falling sudden drops in haemoglobin with concurrent thrombocytopenia, and elevated serum bilirubin, creatinine, urea, or LDH levels.

Renal impairment may not be reversible on treatment discontinuation and dialysis may be required. 3). 6). 5 mg (<1 mmol) of sodium per vial. This should be taken into consideration by patients on a controlled sodium diet. 5 mg (< 1 mmol) sodium per vial.

This should be taken into consideration by patients on a controlled sodium diet.

Hypersensitivity to the active substance or to any of the excipients. 6).