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, firstline 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 1,000 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 1,000 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 1,000 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 1,250 mg/m2 body surface area given as a 30 minute intravenous infusion on Days 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 (1,250 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 1,000 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 count 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 (%)

> 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 reinstated 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 (%)

≥ 1,200 and

> 75,000

100

1,000- < 1,200 or

50,000-75,000

75

700- < 1,000 and

≥ 50,000

50

< 700 or

< 50,000

Omit dose*

*Treatment omitted 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 1,500 (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 (%)

> 1,500 and

≥ 100,000

100

1,000-1,500 or

75,000-100,000

50

< 1,000 or

< 75,000

Omit dose*

*Treatment omitted 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 1,500 (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 neutropenia

• Platelets < 25,000 x 106 /l

• Cycle delay of more than 1 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 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).

Older people (> 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 older people (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 listed in section 6.1.

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 leucopenia, thrombocytopenia 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 and renal impairment insufficiency

Gemcitabine should be used with caution in patients with hepatic or renal function impairment as there is insufficient information from clinical studies to allow clear dose recommendation for this patient population (see section 4.2).

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 impairment.

Laboratory evaluation of renal and hepatic function (including virological tests) should be performed periodically.

Concomitant radiotherapy

Concomitant radiotherapy (given together or ≤ 7 days apart): Toxicity has been reported (see section 4.5 for details and recommendations for use).

Live vaccinations

Yellow fever vaccine and other live attenuated vaccines are not recommended in patients treated with Gemcitabine (see section 4.5).

Posterior reversible encephalopathy syndrome

Reports 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. Acute 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.

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.

Capillary leak syndrome

Capillary leak syndrome has been reported in patients receiving gemcitabine as single agent or in combination with other chemotherapeutic agents (see section 4.8). 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.

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

Haemolytic uraemic syndrome

Clinical findings consistent with the haemolytic uraemic syndrome (HUS) were rarely reported (post-marketing data) in patients receiving Gemcitabine (see section 4.8). HUS is a potentially life-threating disorder. Gemcitabine should be discontinued at the first signs of any evidence of microangiopathic haemolytic anaemia, such as rapidly falling haemoglobin with concomitant thrombocytopenia, 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 powder for solution for infusion 200 mg contains 3.5 mg (<1 mmol) sodium per vial, i.e. essentially sodium free.

Gemcitabine powder for solution for infusion 1000 mg contains 17.5 mg (<1 mmol) sodium per vial, i.e. essentially sodium free.

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 ≤ 7 days apart) - 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) - 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. Fertility, 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% of 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 (≥ 1/10), Common (≥ 1/100 to <1/10), Uncommon (≥ 1/1,000 to <1/100), Rare (≥ 1/10,000 to <1/1,000), Very Rare (<1/10,000).

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

• Leucopenia (Neutropenia 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).

• Thrombocytopenia

• Anaemia

Common

• Febrile neutropenia

Very Rare

• Thrombocytosis

• Thrombotic microangiopathy

Immune system disorders

Very Rare

• Anaphylactoid reaction

Metabolism and nutrition disorders

Common

• Anorexia

Nervous system disorders

Common

• Headache

• Insomnia

• Somnolence

Uncommon

• Cerebrovascular accident

Very Rare

• Posterior reversible encephalopathy syndrome (see section 4.4)

Cardiac disorders

Uncommom

• Arrhythmias, predominantly supraventricular in nature

• Heart failure

Rare

• Myocardial infarct

Vascular disorders

Rare

• Clinical signs of peripheral vasculitis and gangrene

• Hypotension

Very Rare

• Capillary leak syndrome (see section 4.4)

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.)

Gastro-intestinal disorders

Very Common

• Vomiting

• Nausea

Common

• Diarrhoea

• Stomatitis and ulceration of the mouth

• Constipation

Very Rare

• Ischaemic colitis

Hepato-biliary 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

System Organ Class

Frequency grouping

Very Rare

• Toxic epidermal necrolysis

• Stevens-Johnsons Syndrome

Not known

• Pseudocellulitis

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

Infections and infestations

Common

• Infections

Not known

• Sepsis

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.

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)

Thrombocytopenia

0

0

14 (5.3)

1 (0.4)

Neutropenia

11 (4.2)

17 (6.6)*

82 (31.3)

45 (17.2)*

Non-laboratory

Febrile neutropenia

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 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

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)

Thrombocytopenia

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)

Gemcitabin 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)

Neutropenia

19(10.9)

2(1.1)

73(41.7)

50(28.6)

Thrombocytopenia

18(10.3)

2(1.1)

53(30.3)

8(4.6)

Leucopenia

11(6.3)

1(0.6)

84(48.0)

9(5.1)

Non-laboratory

Haemorrhage

0(0.0)

0(0.0)

3(1.8)

0(0.0)

Febrile neutropenia

0(0.0)

0(0.0)

2(1.1)

0(0.0)

Infection without neutropenia

0(0)

0(0.0)

0(0.0)

1(0.6)

Sensory neuropathy was also more frequent in the combination arm than with single-agent carboplatin.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions to the national reported system listed below.

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

4.9. Overdose

There is no known antidote for overdose of Gemcitabine. Doses as high as 5,700 mg/m2 have been administered by intravenous infusion over 30 minutes every 2 weeks with clinically acceptable toxicity. In the event of suspected overdose, the patient should be monitored with appropriate blood counts and receive supportive therapy, as necessary.