GEMCITABINE

Gemcitabine can only be prescribed by a physician qualified in the use of anticancer therapy.

Recommended posology:

Bladder cancer Combination use The recommended dose for gemcitabine is 1000 mg/m2, given by 30-minute intravenous infusion. The dose must be administered 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 D 1 following gemcitabine or D 2 of each 28-day cycle.

This 4-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 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, 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 four-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 days cycle).

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 cancer Combination use To use gemcitabine, in combination with paclitaxel, it is recommended to administer paclitaxel (175 mg/m2) administered 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 monitoringand dose modification due to toxicity Dose modification due to non-haematological toxicity Periodic physical examination and checks of renal and hepatic function must be made to detect non-haematological toxicity.

Gemcitabine 100 mg/ml concentrate for solution for infusion contains 440 mg ethanol anhydrous per ml concentrate. 4). 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, excluded nausea/vomiting, treatment with gemcitabine must be reduced or onsuspended 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 haematological monitoring before each dose Complete Blood Count with Differential and platelet levels.

Prior to the initiation of a cycle, patients must 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 must be adjusted as shown inperform the tables below: 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 the averagest dose of Gemcitabine (%) > 1000 and > 100,000 100 500-1000 or 50,000-100,000 75 < 500 or < 50,000 No 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 at least 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 the averagest dos of Gemcitabine (%) ≥ 1,200 and > 75,000 100 1000- < 1,200 or 50,000-75,000 75 700- < 1000 and ≥ 50,000 50 < 700 or < 50,000 No 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 has reached at least 1,500 (x106/l) and the platelet count has reached 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 (%) > 1,500 and ≥ 100,000 100 1000-1,500 or 75,000-100,000 50 < 1000 or < 75,000 No dose* *Treatment omitted will not be re-instated within a cycle.

Treatment will start begin on day 1 of the next cycle once the […]

The most commonly reported adverse drug reactions associated with Gemcitabine treatment include: nausea with or without vomiting, elevated 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 10-40% of patients (higher 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 follows: very common (≥1/10), vommon (≥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 from the based on available data).

The table below displaying the adverse reactions and their frequency 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).

4) • Bronchospasm – usually mild and transient but may require parenteral treatment. 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. Oedema is usually reversible after stopping treatment. System Organ Class Frequency grouping Common • Fever • Asthenia • Chills Rare • Injection site reactions – mainly mild in nature.

5). • Radiation recall Combination use in breast cancer 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 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. 0 % of patients enrolled in the arm receiving paclitaxel.

4) 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) […]

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 leucopenia, 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.

Renal and hepatic insufficiency Administration of gemcitabine in patients with concurrent liver metastases or a preexisting medical history of hepatitis, alcoholism or liver cirrhosis may lead to exacerbation of the underlying hepatic insufficiency.

Laboratory evaluation of renal and hepatic function (including virological tests) should be performed periodically. 2). 5 for details and recommendations for use). 5). Cardiovascular events 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. Posterior reversible encephalopathy syndrome Cases 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.

Severe 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.

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 develop, consideration should be made to discontinuing gemcitabine therapy.

Early use of supportive care measure may help ameliorate the patient’s condition. 8). HUS is a potentially life-threatening condition. Gemcitabine should be discontinuedat the first signs of microangiopathic haemolytic anaemia, such as sudden drop in haemoglobin with concomitant thrombocytopenia, elevation of serum bilirubin, serum creatinine, blood urea nitrogen, or LDH.

Renal failure may not be reversible on treatment discontinuation and dialysis may be required. 3). 6). 68 mmol) of sodium per maximum daily dose (2250 mg). This should be taken into consideration by patients on a controlled sodium diet.

Ethanol Gemcitabine 100 mg/ml concentrate for solution for infusion contains 440 mg ethanol anhydrous per ml concentrate. This may be harmful in patients suffering from […]

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