1. Name Of The Medicinal Product
Gemcitabine 38mg/ml powder for solution for infusion
2. Qualitative And Quantitative Composition
One ml of the reconstituted solution for infusion (see section 6.6) contains 38mg gemcitabine (as hydrochloride).
200 mg vial:
Each vial contains 200mg of gemcitabine (as hydrochloride).
Contains approximately 0.15mmol (3.56mg) sodium per 200mg vial.
1 g vial:
Each vial contains 1g of gemcitabine (as hydrochloride).
Contains approximately 0.77mmol (17.81mg) sodium per 1g vial.
2 g vial:
Each vial contains 2g of gemcitabine (as hydrochloride).
Contains approximately 1.54mmol (35.62mg) sodium per 2g vial.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Powder for solution for infusion.
White or almost white compact aggregate. After reconstitution in sodium chloride 0.9% the solution is clear to pale opalescent and colourless to pale yellow.
The pH of the reconstituted solution in sodium chloride 0.9% solution is 3.0 ± 0.3.
The osmolarity of the reconstituted solution (38mg/ml of gemcitabine (as hydrochloride) in sodium chloride 0.9% solution) is 775 mOsm/l.
4. Clinical Particulars
4.1 Therapeutic 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.
4.2 Posology And Method Of Administration
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 1000mg/m2, given by 302 on Day 1 following gemcitabine or day 2 of each 28
Pancreatic cancer
The recommended dose of gemcitabine is 1000mg/m2, given by 30
Non small cell lung cancer
Monotherapy
The recommended dose of gemcitabine is 1000mg/m2, given by 30
Combination use
The recommended dose for gemcitabine is 1250mg/m2 body surface area given as a 30
Cisplatin has been used at doses between 75-100mg/m2 once every 3 weeks.
Breast cancer
Combination use
Gemcitabine in combination with paclitaxel is recommended using paclitaxel (175mg/m2) administered on Day 1 over approximately 32) as a 306/l) prior to initiation of gemcitabine + paclitaxel combination.
Ovarian cancer
Combination use
Gemcitabine in combination with carboplatin is recommended using gemcitabine 1000mg/m2 administered on Days 1 and 8 of each 21
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 account 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:
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*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).
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*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).
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*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 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 days
• Febrile neutropaenia
• Platelets < 25,000 x 106/l
• Cycle delay of more than 1 week due to toxicity
Method of administration
The medicinal product 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 renal or hepatic 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 the active substance 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 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 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 made to discontinuing gemcitabine therapy. Early use of supportive care measure 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). 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.
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
Vial of 200mg gemcitabine contains 3.56mg (<1mmol) sodium.
Vial of 1g gemcitabine contains 17.81mg (< 1mmol) sodium.
Vial of 2g gemcitabine contains 35.62mg (1.54mmol) sodium.
This should be taken into consideration by patients on a controlled sodium 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 2 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 (600mg/m2, four times) and cisplatin (80mg/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.
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 women. 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 after all.
Breast-feeding
It is not known whether gemcitabine is excreted in human milk and adverse effects 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 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
The frequency and severity of the adverse reactions are affected by the dose, infusion rate and intervals between doses (see section 4.4). Dose
Clinical trial data
Frequencies are defined as: Very common (
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.
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Postmarketing experience (spontaneous reports) frequency not known (can't 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, Steven-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.
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*Grade 4 neutropaenia 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
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Combination use in ovarian cancer
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