1. Name Of The Medicinal Product
Gemcitabine 200mg Powder for Solution for Infusion
Gemcitabine 1g Powder for Solution for Infusion
Gemcitabine 2g Powder for Solution for Infusion
2. Qualitative And Quantitative Composition
One vial contains gemcitabine hydrochloride, equivalent to 200 mg gemcitabine.
One vial contains gemcitabine hydrochloride, equivalent to 1 g gemcitabine.
One vial contains gemcitabine hydrochloride, equivalent to 2 g gemcitabine.
After reconstitution, the solution contains 38 mg/ml gemcitabine (as hydrochloride).
Excipients
Each 200 mg vial contains approximately 3.5 mg (0.15 mmol) sodium.
Each 1 g vial contains approximately 17.5 mg (0.75 mmol) sodium.
Each 2 g vial contains approximately 35 mg (1.5 mmol) sodium.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Powder for solution for infusion (powder for infusion)
White to off-white plug or powder.
4. Clinical Particulars
4.1 Therapeutic Indications
Bladder Cancer:
Locally advanced or metastatic bladder cancer, in combination with cisplatin.
Pancreatic Cancer:
Locally advanced or metastatic adenocarcinoma of the pancreas.
Non-Small Cell Lung Cancer:
First-line treatment of patients with locally advanced or metastatic non-small cell lung cancer, in combination with cisplatin. Gemcitabine monotherapy can be considered in elderly patients or those with performance status 2.
Ovarian Cancer:
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.
Breast Cancer:
Unresectable, locally recurrent or metastatic breast cancer, in combination with paclitaxel, in patients experiencing a relapse after adjuvant/neoadjuvant chemotherapy. The preceding chemotherapy should have included an anthracycline, unless clinically contraindicated.
4.2 Posology And Method Of Administration
For intravenous infusion, following reconstitution. Upon reconstitution a colourless or slightly yellow solution is produced.
Gemcitabine should only be prescribed by a physician qualified in the use of anti-cancer chemotherapy.
Bladder cancer (combination therapy):
Adults: The recommended dose for gemcitabine 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 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 four week cycle is then repeated. Dosage reduction with each cycle or within a cycle may be applied, based upon the amount of toxicity experienced by the patient.
Pancreatic Cancer:
Adults: 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 one week rest period. Subsequent cycles should consist of gemcitabine infusions once weekly for 3 consecutive weeks out of every four weeks. Dosage reduction with each cycle or within a cycle may be applied, based upon the amount of toxicity experienced by the patient.
Non-small cell lung cancer (monotherapy):
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 with each cycle or within a cycle may be applied, based upon the amount of toxicity experienced by the patient.
Non-small cell lung cancer (combination therapy):
Adults: The recommended dose of gemcitabine is 1250 mg/m2, given by 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 applied, based upon the amount of toxicity experienced by the patient.
Cisplatin has been used at doses between 75-100 mg/m2 once every 3 weeks.
Ovarian cancer (combination therapy):
The recommended dose of gemcitabine, when used in combination with carboplatin, is 1000 mg/m2, given by 30 minute intravenous infusion on days 1 and 8 of each 21 day cycle. After gemcitabine, carboplatin will be given on day 1, consistent with a target Area Under Curve (AUC) of 4.0mg/ml/min. Dosage reduction with each cycle or within a cycle may be applied, based upon the amount of toxicity experienced by the patient.
Breast cancer (combination therapy):
Adults: It is recommended that gemcitabine is used together with paclitaxel according to the following procedure:
Paclitaxel (175 mg/m2) is intravenously infused over 3 hours on day 1, followed by gemcitabine (1250 mg/m2) intravenously infused for 30 minutes on days 1 and 8 of each 21 day treatment cycle. Dosage reduction with each cycle or within a cycle may be applied based upon the amount of toxicity experienced by the patient. The absolute granulocyte count should be at least 1.5 x 109/l before treatment with the gemcitabine + paclitaxel combination.
Monitoring for toxicity and dose modification due to toxicity
Dosage adjustment 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 amount 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 been resolved.
For cisplatin, carboplatin, and paclitaxel dosage adjustment in combination therapy, please refer to the corresponding Summary of Product Characteristics.
Dosage adjustment in the presence of haematological toxicity:
Initiation of a cycle
For all indications, patients must be monitored before each dose for platelet and granulocyte counts. Patients should have an absolute granulocyte count of at least 1,500 (x106/l) and a platelet count of 100,000 (x106/l) prior to the administration of a cycle.
Within a cycle
Dose modifications of gemcitabine within a cycle should be performed according to the following tables:
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*Withheld treatment will not be reinstated within a cycle before the absolute granulocyte count reaches at least 0.5(x 109/l) and the platelet count reaches 50 (x 109/l).
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*Withheld treatment 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 1.5(x 109/l) and the platelet count reaches 100 (x 109/l)
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*Withheld treatment 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 1.5 (x 109/l) and the platelet count reaches 100 (x 109/l).
Dose adjustment 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 haematological toxicities:
• Absolute granulocyte count < 0.5 x 109/l for more than 5 days
• Absolute granulocyte count < 0.1 x 109/l for more than 3 days
• Febrile neutropaenia
• Platelets <25 x 109/l
• Cycle delay of more than one week due to toxicity
Method of administration
Gemcitabine 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.
For instructions on reconstitution, see section 6.6
Special Populations
Patients with hepatic or renal impairment:
Gemcitabine 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 (see sections 4.4 and 5.2).
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 (see section 5.2).
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.
4.3 Contraindications
Hypersensitivity to gemcitabine or to any of the excipients
Breast-feeding (see section 4.6)
4.4 Special Warnings And Precautions For Use
Prolongation of the infusion time and increased dosing frequency have been shown to increase toxicity.
Haematological toxicity
Gemcitabine can suppress bone marrow function as manifested by leucopaenia, thrombocytopaenia, 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 (see section 4.2). 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.
Hepatic insufficiency
Administration of gemcitabine to patients with concurrent liver metastases or a pre-existing medical history of hepatitis, alcoholism or cirrhosis of the liver may result in exacerbation of the underlying liver insufficiency.
Laboratory evaluation 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 (see section 4.2).
Concomitant radiotherapy
Concomitant radiotherapy (given together or
Live vaccinations
Yellow fever vaccine and other live attenuated vaccines are not recommended in patients treated with gemcitabine (see section 4.5).
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.
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. The aetiology of these effects is unknown. If such effects develop, consideration should be given to discontinuing gemcitabine therapy. Early use of supportive care measures may help ameliorate the condition.
Renal
Clinical findings consistent with the haemolytic uraemic syndrome (HUS) were rarely reported in patients receiving gemcitabine (see section 4.8). Treatment should be discontinued at the first signs of any evidence of micro-angiopathic haemolytic anaemia, such as rapidly falling haemoglobin levels with concurrent thrombocytopenia, elevation of serum bilirubin, serum creatinine, blood urea nitrogen or lactate dehydrogenase (LDH). Renal failure may not be reversible with discontinuation of therapy, and dialysis may be required.
Fertility
In fertility studies, gemcitabine caused hypospermatogenesis in male mice (see section 5.3). 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 (see section 4.6).
Sodium
Gemcitabine 200 mg contains 3.5 mg (0.15 mmol) sodium per vial. This should be taken into consideration by patients on a sodium-controlled diet.
Gemcitabine 1 g contains 17.5 mg (0.75 mmol) sodium per vial. This should be taken into consideration by patients on a sodium-controlled diet.
Gemcitabine 1 g contains 35 mg (1.5 mmol) sodium per vial. This should be taken into consideration by patients on a sodium-controlled diet.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
No specific interaction studies have been performed (see section 5.2)
Radiotherapy
Concurrent (given together or - 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) - Available information 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.
Others
Yellow fever and other live attenuated vaccines are not recommended due to the risk of systemic, possibly fatal, disease, particularly in immunosuppressed patients.
4.6 Pregnancy And Lactation
Pregnancy:
There are no adequate data from the use of gemcitabine in pregnant patients. Studies in animals have shown reproductive toxicity (see section 5.3). Based on results from animal studies and the mechanism of action of gemcitabine, this substance should not be used during pregnancy, unless clearly necessary. Women should be advised not to become pregnant during treatment with gemcitabine and to warn their attending physician immediately, should this occur.
Lactation:
It is not known whether gemcitabine is excreted in human milk and adverse events on the suckling child cannot be excluded. Breast-feeding must be discontinued during gemcitabine therapy.
Fertility:
In fertility studies, gemcitabine caused hypospermatogenesis in male mice (see section 5.3). 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.
4.7 Effects On Ability To Drive And Use Machines
No studies on the effects on the ability to drive and use machines have been performed. However, gemcitabine has been reported to cause mild to moderate somnolence, especially in combination with alcohol consumption. Patients should be cautioned against driving or operating machinery until it is established that they do not become somnolent.
4.8 Undesirable Effects
The most commonly reported adverse reactions associated with gemcitabine treatment include: nausea, with or without vomiting, and raised liver transaminases (aspartate aminotransferase (AST)/alanine aminotransferase (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 (highest incidence in lung cancer patients); allergic skin rashes occurring in approximately 25% of patients, and 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 (see section 4.4). Dose-limiting adverse reactions are reductions in thrombocyte, leucocyte, and granulocyte counts (see section 4.2).
The following table of undesirable effects and frequencies is based on clinical trials. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Frequencies are defined as: Very common (
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Post-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 (see section 4.4)
Gastrointestinal disorders
Ischaemic colitis
Hepatobiliary 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 (see section 4.4)
Haemolytic uraemic syndrome (see section 4.4)
Injury, poisoning and procedural complications
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.
Grade 3 and 4 Adverse Events. Paclitaxel versus gemcitabine plus paclitaxel:
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* 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 cancer
Grade 3 and 4 Adverse Events. MVAC versus gemcitabine plus cisplatin:
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Combination use in ovarian cancer
Grade 3 and 4 Adverse Events. Carboplatin versus gemcitabine plus carboplatin:
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