1. Name Of The Medicinal Product
Gemcitabine SUN 200 mg, powder for solution for infusion
Gemcitabine SUN 1000 mg, powder for solution for infusion
2. Qualitative And Quantitative Composition
[For 200 mg strength:]
Each vial contains 200 mg gemcitabine (as hydrochloride)
Excipient:
Each vial contains 3.5 mg sodium.
[For 1000 mg strength:]
Each vial contains 1000 mg gemcitabine (as hydrochloride)
Excipient:
Each vial contains 17.5 mg sodium.
One ml of the reconstituted solution for infusion contains 38 mg gemcitabine (as hydrochloride).
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Powder for solution for infusion.
White to off-white lyophilized cake.
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 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.
Breast cancer
Combination use
Gemcitabine in combination with paclitaxel is recommended using 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. 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. After gemcitabine, carboplatin will be given on Day 1 consistent with a target Area under curve (AUC) of 4.0 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 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:
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 SUN (%)
|
|
> 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 SUN (%)
|
|
> 1,200
|
and
|
>75,000
|
100
|
1,000-<l,200
|
or
|
50,000-75,000
|
75
|
700-<l,000
|
and
|
|
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 SUN (%)
|
|
> 1,500
|
and
|
|
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 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 x106/l
• Cycle delay of more than 1 week due to toxicity
Method of administration
Gemcitabine SUN 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
Gemcitabine SUN 200 mg contains 3.5 mg (<1 mmol) sodium per vial. This should be taken into consideration by patients on a controlled sodium diet.
Gemcitabine SUN 1000 mg contains 17.5 mg (< 1 mmol) sodium per vial. 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 (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)- 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 SUN 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.
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).
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.
System Organ Class
|
Frequency grouping
|
Blood and lymphatic system disorders
|
Very common
• Leucopaenia (Neutropaenia Grade 3 = 19.3%; Grade 4 = 6%).
Bone-marrow suppression is usually mild to moderate and mostly affects the granulocyte count (see section 4.2)
• Thrombocytopaenia
• Anaemia
Common
• Febrile neutropaenia
Very rare
• Thrombocytosis
|
Immune system disorders
|
Very Rare
• Anaphylactoid reaction
|
Metabolism and nutrition disorders
|
Common
• Anorexia
|
Nervous system disorders
|
Common
• Headache
• Insomnia
• Somnolence
Uncommon
• Cerebrovascular accident
|
Cardiac disorders
|
Uncommon
• Arrhythmias, predominantly supraventricular in nature
• Heart failure
Rare
• Myocardial infarct
|
Vascular disorders
|
Rare
• Clinical signs of peripheral vasculitis and gangrene
• Hypotension
|
Respiratory, thoracic and mediastinal disorders
|
Very common
• Dyspnoea -usually mild and passes rapidly without treatment
Common
• Cough
• Rhinitis
Uncommon
• Interstitial pneumonitis (see section 4.4)
• Bronchospasm -usually mild and transient but may require parenteral treatment
Rare
• Pulmonary oedema
• Adult respiratory distress syndrome (see section 4.4)
|
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
• Lyell's syndrome (toxic epidermal necrolysis)
• Stevens-Johnson Syndrome
|
Musculoskeletal and connective tissue disorders
|
Common
• Back pain
• Myalgia
|
Renal and urinary disorders
|
Very Common
• Haematuria
• Mild proteinuria
Uncommon
• Renal failure (see section 4.4)
• Haemolytic uraemic syndrome (see section 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 oedema-including facial oedema. Oedema is usually reversible after stopping treatment
Common
• Fever
• Asthenia
• Chills
Rare
• Injection site reactions-mainly mild in nature
|
Injury, poisoning, and procedural Complications
|
Rare
• Radiation toxicity (see section 4.5).
• 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.
Grade 3 and 4 Adverse Events
Paclitaxel versus gemcitabine plus paclitaxel
|
|
|
|
|
|
Number (%) of Patients
|
|
|
|
|
Paclitaxel arm
(N=259)
|
Gemcitabine plus Paclitaxel arm
(N=262)
|
|
|
|
Grade 3
|
Grade 4
|
Grade 3
|
Grade 4
|
Laboratory
|
|
|
|
|
Anaemia
|
5 (1.9)
|
1 (0.4)
|
15 (5.7)
|
3 (1.1)
|
Thrombocytopaenia
|
0
|
0
|
14 (5.3)
|
1 (0.4)
|
Neutropaenia
|
11 (4.2)
|
17 (6.6)*
|
82 (31.3)
|
45 (17.2)*
|
Non-laboratory
|
|
|
|
|
Febrile neutropaenia
|
3 (1.2)
|
0
|
12 (4.6)
|
1 (0.4)
|
Fatigue
|
3 (1.2)
|
1 (0.4)
|
15 (5.7)
|
2 (0.8)
|
Diarrhoea
|
5 (1.9)
|
0
|
8 (3.1)
|
0
|
Motor neuropathy
|
2 (0.8)
|
0
|
6 (2.3)
|
1 (0.4)
|
Sensory neuropathy
|
9 (3.5)
|
0
|
14 (5.3)
|
1 (0.4)
|
*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
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 in ovarian cancer
Grade 3 and 4 Adverse Events
Carboplatin versus Gemcitabine plus carboplatin
|
|
|
|
|
|
Number (%) of Patients
|
|
|
|
|
Carboplatin arm
(N=174)
|
Gemcitabine plus carboplatin arm
(N=175)
|
|
|
|
Grade 3
|
Grade 4
|
Grade 3
|
Grade 4
|
Laboratory
|
|
|
|
|
Anaemia
|
10 (5.7)
|
4 (2.3)
|
39 (22.3)
|
9 (5.1)
|
Neutropaenia
|
19 (10.9)
|
2 (1.1)
|
73 (41.7)
|
50 (28.6)
|
Thrombocytopaenia
|
18 (10.3)
|
2 (1.1)
|
53 (30.3)
|
8 (4.6)
|
|
