Gemcitabine 2 g Powder for Solution for Infusion – Summary of Product Characteristics (SmPC) for healthcare professionals

1 NAME OF THE MEDICINAL PRODUCT

Gemcitabine 2 g Powder for Solution for Infusion

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

One vial contains gemcitabine hydrochloride equivalent to 2 g gemcitabine. After reconstitution, the solution contains 38 mg/ml of gemcitabine.

Excipients

Each 2 g vial contains 35 mg (1.52 mmol) sodium.

For a full list of excipients see section 6.1.

3 PHARMACEUTICAL FORM

Powder for solution for infusion.

White to off-white plug or powder.

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 the 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 a performance status of 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 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 can only be prescribed by a physician qualified in the use of anti-cancer therapy.

Recommended posology

Bladder cancer

Combination use

The recommended dose for gemcitabine is 1000 mg/m², as a 30-minute intravenous infusion. The dose must be administered on Days 1, 8 and 15 for a 28-day cycle in combination with cisplatin. Cisplatin is given at the recommended dose of 70 mg/m² on D 1 following gemcitabine or D2 of each 28-day cycle. This 4four-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 is 1000 mg/m², administered as a 30-minute intravenous infusion. The administration should be repeated once weekly for 7 consecutive weeks followed by one-week of rest. From the next cycle, the administration must be repeated once weekly for 3 consecutive weeks every 4 weeks. Dosage reduction with each cycle or within a cycle may be considered based upon the grade of toxicity experienced by the patient.

Non small Cell lung cancer

Monotherapy

The recommended dose 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 4four-week cycle is then repeated. Dosage reduction with each cycle or within a cycle may beconsidered 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 cycles ). Dosage reduction with each cycle or within a cycle may be considered 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) 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. Carboplatin is to be administered after gemcitabine, on day 1 at a dosage that allows a target AUC of 4.0 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 monitoring and 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. 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, excluding nausea/vomiting, treatment with gemcitabine must be reduced or suspended 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 hematological monitoring before each dose: Complete Blood count with Differential and platelet. Prior to the initiation of a cycle, patients must have an absolute granulocyte count of at least 1,500 (x 10⁶/L) and a platelet count of 100,000 (x 10⁶/L

Within a cycle

Dose modifications of gemcitabine within a cycle must be adjusted as shown in to the tables below:

* Omitted treatment is not to 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).

*Omitted treatment is not to 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).

* Omitted treatment is not to be re-instated within a cycle. Treatment will begin 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 modifications in the following cycles due to haematological toxicity for all indications

The dose of gemcitabine must be reduced to 75% of the initial dose of the first cycle, in the event that the following haematological toxicities are observed:

• 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 over one week due to toxicity

Method of administration

Gemcitabine is well-tolerated during infusion and can be administered Ifas outpatient care. In the event ofextravasation the infusion must generally be stopped immediately and re-administered ina different vein. The patient must be closely monitored after administration.

For reconstitution instructions, see section 5.6.

Special populations

Patients with renal impairment or hepatic impairment

Gemcitabine must be administered with caution in patients with hepatic or renal impairment as there is insufficient information from clinical studies to allow for clear recommendations regarding the doses to be administerd in these patient populations (see sections 4.4 and 5.2).

Elderly patients (> 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).

Children (< 18 years)

Gemcitabine is not recommended for use in children under 18 years of age due to insufficient data on safety and efficacy.

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 manifesteding leucopaenia, thrombocytopaenia and anaemia.

Patients receiving gemcitabine must under monitoring, including for platelet, leukocyte and granulocyte counts prior to each dose. Treatment interruption or modification must be considered each time drug-induced bone marrow toxicity is detected (see section 4.2). However, myelosuppression is short lived and usually does not require a dose reduction and only rarely requires discontinuation. Blood counts may continue to decrease after cessation of treatment with gemcitabine. The treatment must be initiated with caution in patients with impaired bone marrow function, As with other cytolytic treatments, the risk of cumulative bone-marrow suppression must be taken into consideration in cases of combined or sequentialchemotherapy.

Hepatic impairment and renal impairment

.

Gemcitabine must be used with caution in patients with hepatic or renal impairment as there is insufficient information from clinical studies to allow for clear recommendation regarding the doses to be administered in these patient populations (see section 4.2).

The administration of gemcitabine in patients who also have liver metastases or a history of hepatitis, alcoholism or cirrhosis may results in exacerbation of underlying hepatic impairment.

Renal and hepatic function must be checked periodically (including virology testing). Concomitant radiotherapy

Concomitant radiotherapy (given simultaneously or with an interval of ≤7 days): toxicity reported (see section 4.5 for details and recommendations for use).

Live vaccinations

The yellow fever vaccine and other live attenuated vaccines are not recommended in patients being treated with gemcitabine (see section 4.5).

Cardiovascular

Due to the risk of cardiac and/or vascular disorders on gemcitabine, special attention must be paid to patients with a history of cardiovascular events.

Capillary leak syndrome (CLS)

Capillary leak syndrome has been reported in patients receiving gemcitabine alone or in combination with anti-cancer agents(see section 4.8). In general, treatments for this conditions exists if it is diagnosed early and treated appropriately, but fatal cases have been reported. Thiscondition casues systemic capillary hyperpermeability with leakage of fluid and proteins from the intravascular space into the interstitium. The clinical characterstics include generalized oedema, weight gain, hypoalbuminaemia, severe hypotension, acute renal failure and pulmonary oedema. Gemcitabine must be stopped and symptomatic treatment must be initiated if capillary leak syndrome occurs during treatment. Capillary leak syndrome may occur during subsequent cycles has been associated with adult respiratory distress syndrome in the literature.

Posterior reversible encephalopathy syndrome

Cases of posterior reversible encephalopathy syndrome (PRES) with potentially severe consequences have been reported in patients receiving gemcitabine alone or in combination with other anti-cancer agents. Severe hypertension and seizure have been reported in the majority of pateients receiving gemcitabine who experienced PRES, but other symptoms such as headaches, lethargy, confusion and blindness may also be present.The diagnosis is ideally confirmed through magnetic resonance imaging (MRI). PRES was generally reversible with appropriate. symptomatic treatment If PRES develops during treatment, gemcitabine must be permanently discontinued and symptomatic treatments mus be initiated such as blood pressure control and anti-seizure medication.

Pulmonary

Pulmonary effects, which are sometimes severe (such as pulmonary oedema, interstitial lung disease adult respiratory distress syndrome (ARDS)) have been reported in association with gemcitabinetreatment. If such effects occur, discontinuation of treatment with gemcitabineshould be considered. Early initiation of supportive measures may help to improve the patient’s condition.

Renal

Haemolytic uraemic syndrome

Clinical sings consistent with haemolytic uraemic syndrome (HUS) have been reported in rare cases (post-marketing data) in patients receiving gemcitabine (see section 4.8). HUS is a potentially life-threatening condition Gemcitabine must be stopped at the first signs of microangiopathic haemolytic anaemia, such as falling sudden drops in haemoglobin with concurrent thrombocytopenia, and serum bilirubin, creatinine, urea, or LDH levels. Renal impairment may not be reversible on treatment discontinuation and dialysis may be required.

Fertility

In fertility studies gemcitabine caused hypospermatogenesis in male mice (see section 5.3). Mentreated with gemcitabine are therefore advised not to father a child during and in the 3months following treatment and to seek additional information on cryopreservation of sperm before beginning treatment due to the possibility of infertility related to gemcitabine (see section 4.6).

Sodium

Gemcitabine 2 g powder for solution for infusion contains 35 mg (1.52 mmol)of sodium per vial. This should be taken into consideration by patients on a controlled sodium diet.

4.4 Special warnings and precautions for use

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, manifesting as leucopaenia, thrombocytopaenia and anaemia.

Patients receiving gemcitabine should be monitored prior to each dose, including for platelet, leukocyte and granulocyte counts. Treatment interruption or modification mustbe considered each time drug-induced bone marrow toxicity is detected (see section 4.2). However, myelosuppression is short lived and usually does not require a dose reduction and only rarely requires discontinuation.

Blood counts may continue to decrease after cessation of treatment with gemcitabine. The treatment must be initiated with caution in patients with impaired bone marrow function,

As with other cytolytic treatments, the risk of cumulative bone-marrow suppression taken into consideration in cases of combined or sequential chemotherapy.

Hepatic impairment and renal impairment

Gemcitabine mustbe used with caution in patients with or renal impairmentas there is insufficient information from clinical studies to allow for clear recommendation regarding the doses to be administered in these patient populations (see section 4.2).

The administration of gemcitabine in patients who also have liver metastases or a history of hepatitis, alcoholism or cirrhosis may results in exacerbation of underlying hepatic impairment.

Renal and hepatic function must be checked periodically (including virology testing).

Concomitant radiotherapy

Concomitant radiotherapy (given simultaneously or with an interval of ≤7 days) toxicity has been reported (see section 4.5 for details and recommendations for use).

Live vaccinations

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

Cardiovascular

Due to the risk of cardiac and/or vascular disorders ongemcitabine, special attention must be paid topatients with a history of cardiovascular events.

Capillary leak syndrome

Cases of capillary leak syndrome have been reported in patients receiving gemcitabine alone or in combination with other anti-cancer agents(see section 4.8). In general, treatments for this condition exist if it is diagnosed early and treated appropriately, but fatal cases have been reported. Thiscondition involves causes systemic capillary hyperpermeability, with leakage of fluid and proteins from the intravascular space into the interstitium. The clinical characterstics include generalised oedema, weight gain, hypoalbuminaemia, severe hypotension, acute renal failure and pulmonary oedema. Gemcitabine must be stopped and symptomatic treatments must be initiated if capillary leak syndrome occurs during treatment. Capillary leak syndrome may occur during subsequent cycles and has been associated with adult respiratory distress syndrome in the literature.

Posterior reversible encephalopathy syndrome ()

Cases of posterior reversible encephalopathy syndrome (PRES) with potentially severe consequences have been reported in patients receiving gemcitabine alone or in combination with other chemotherapeutic anti-cancer agents. Severe hypertension and seizures have been reported in the majority of patients receiving gemcitabine who experiencedPRES, but other symptoms, such as headaches. Lethargy, confusion and blindness may also be present. The diagnosis is ideally confirmed through magnetic resonance imaging (MRI). PRES was generally reversible with appropriate symptomatic treatment. If PRES develops during treatment,. gemcitabine mustbe permanently discontinued and symptomatic treatments must be initiated such as blood pressure control and anti-seizure medication.

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 occur, discontinuation of treatment with gemcitabine should be considered. Early initiation of supportive measures may help to improve the patient’s condition.

Renal

Haemolytic uraemic syndrome

Clinical signs consistent with haemolytic uraemic syndrome (HUS) have beenreported in rare cases (post-marketing data) in patients receiving gemcitabine (see section 4.8). HUS is a potentially life-threatening condition. Gemcitabine must be stopped at the first signs of microangiopathic haemolytic anaemia, such as falling sudden drops in haemoglobin with concurrent thrombocytopenia, and elevated serum bilirubin, creatinine, urea, or LDH levels. Renal impairment may not be reversible on treatment discontinuation and dialysis may be required.

Fertility

In fertility studies gemcitabine caused hypospermatogenesis in male mice (see section 5.3). Men treated with gemcitabine are therefore advised not to father a child during and in the 3months following treatment and to seek additional information on cryopreservationof sperm before beginning treatment due tothe possibility of infertility related to gemcitabine (see section 4.6).

Sodium

Gemcitabine 200 mg powder for solution for infusion contains 3.5 mg (<1 mmol) of sodium per vial. This should be taken into consideration by patients on a controlled sodium diet.

Gemcitabine 1 g powder for solution for infusion 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 conducted (see section 5.2)

Radiotherapy

Concomitant use (given simultaneously or with an interval of ≤7 days) - The toxicity related to this multimodality therapy is depends on numerous different factors, including the dose of gemcitabine, its frequency of administration, the dose of radiation, the radiotherapy planning technique, the target tissue, and the target volume. Pre-clinical and clinical studies have demonstrated that gemcitabine has radiosensitising activity. In one clinical on patients with non-small cell lung cancer , where gemcitabine was administered at a dose of 1,000 mg/m² concomitantly with thoracic radiotherapy for a duration of up to 6 consecutive weeks, significant toxicity in the form of severe, potentially life threatening mucositis, including oesophagitis, and pneumonitis were observed, particularly in patients who received large volumes of radiotherapy [median treatment volume 4,795 cm³]. Subsequent studies have suggested that gemcitabine may feasibly be administered with radiotherpay at lower doses with predictable toxicity, as was the case in one a a phase II study in non-small cell lung cancer, in which doses of thoracic radiotherapy of 66 Gy were concomitantly with gemcitabine (600 mg/m², four times) and cisplatin (80 mg/m² twice) for 6 weeks. The optimum regimen for safe administration of

gemcitabine with therapeutic doses of radiotherapy has not yet been determined in all tumour types.

Non- concomitant (administered with an interval of>7 days - Analysis of the data does not indicate that toxicity increases when gemcitabine is administered more than 7 days before or afterradiotherapy, other than radiation recall.The data suggest that gemcitabine can be initiated after the acute effects of radiation therapy have resolved or at least one week after radiation.

Radiation injury has been reported in the target tissues ( for example. oesophagitis, colitis, and pneumonitis) whether or not gemcitabine was administered concomitantly with the radiotherapy.

Others

The yellow fever vaccine and live attenuated vaccines are not recommended due to the risk of potentially fatal systemic, , disease, particularly in immunosuppressed patients.

4.6 Pregnancy and lactation

Women of childbearing age / contraception in men and women

Due to the genotoxic potential of gemcitabine (see section 5.3), women of childbearing age must use effective methods of contraception during treatment with gemcitabine and for 6 months after treatment discontinuation.

Men must be advised to use effective methods of contraception and not to father a child during treatment with gemcitabine and in the 3 months following its discontinuation.

Pregnancy

There is insufficient data on the use of gemcitabine in pregnant women. Animal studies in animals have demonstrated reproductive toxicity (see section 5.3). Based on the results of animal studies and on the mechanism of action of gemcitabine, this product must not be used during pregnancy except where necessary. Patients must be informed of the risk related not to treatment with gemcitabine during pregnancy, and mustimmediately, inform their doctor in the event of pregnancy.

Breast-feeding

It is unknown whether gemcitabine passes into the breast milk and adverse effects on the foetus have not been ruled out. Breast-feeding must be stopped during treatment with gemcitabine.

Fertility

In fertility studies gemcitabine caused hypospermatogenesis in male mice (see section 5.3). Therefore, men treated with gemcitabine are therefore advised not to father a child during and in the 3 months following treatment and to seek additional information on cryopreservation of sperm before beginning treatment due to the possibility of infertility related to gemcitabine.

4.7 Effects on ability to drive and use machines

The effects on ability to drive and use machines have not been studied . However, it has been reported that gemcitabine can cause mild to moderate drowsiness, particularly in combination with alcohol consumption. Patients must be advised against driving or using machines until it is observed that are no longer drowsy.

4.8 Undesirable effects

The most commonly reported adverse reactions associated with Gemcitabine include: nausea with or without vomiting, elevated liver transaminases (AST/ALT) and alkaline phosphatase levels, reported in approximately 60% of patients; proteinuria and haematuria reported in approximately 50% of patients; dyspnoea reported in 10 to 40% of patients (higher incidence rate in patients with lung cancer); allergic drug eruptions, occurring in approximately 25% of patients and are associated with pruritusin 10% of patients.

The frequency and severity of adverse reactions depends onthe dose, the infusion rate and the intervals between doses (see section 4.4). Dose-limiting adverse reactions are : reduced platelets, leukocyte and granulocyte counts (see section 4.2).

Data from clinical studiesFrequencies are defined as follows: Very common (≥1/10), common (≥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 based on available data).

The table below displaying the adverse reactions and their frequency is based on data from clinical studies. Within each frequency grouping, adverse reactionsare presented in order of decreasing seriousness.

Rare

• Ulceration
• Blister and sore formation
• ScalingDesquamation
• Severe skin reactions, including desquamation and bullous eruptions

Very rare

• Toxic epidermal necrolysis
• Stevens-Johnson syndrome

Not known

• Pseudocellulitis.
• Acute generalized exanthematous pustulosis.

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 toxicity, including neutropenia, increases when gemcitabine is administeredin combination with paclitaxel. However, the increased frequency of these adverse reactions is not associated with an increased rate of infectiousor haemorrhagic events. Fatigue and febrile neutropaenia occur more frequently when gemcitabine is adminstered in combination with paclitaxel. Fatigue, not associated with anaemia, generally resolves after the first cycle.

Grade 3 and 4 Adverse Reactions

*Grade 4 neutropaenia persisting for over 7 days was reported in 12.6% of patients in the gemcitabine-paclitaxel combination arm and 5.0% of patients enrolled in the arm receiving paclitaxel

Combination use in bladder cancer

Combination use in ovarian cancer

Sensory neuropathy was most commonly reported in the carboplatin combination arm than with Carboplatin monotherapy

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 via Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9 Overdose

There is no known antidote for overdose of gemcitabine. Doses of up to 5700 mg/m² have been administered as 30-minutes IV infusion every two weeks with acceptable clinical toxicity. Ifoverdose, is suspected the patient must undergo monitoring including appropriate blood counts and receive supportive therapy, as necessary.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: pyrimidine analogues ATC code: L01BC05

Cytotoxic activity in cell cultures

Gemcitabine shows significant cytotoxic effects against a variety of cultured murine and human tumour cells. Its action is phase-specific such that gemcitabine primarily kills cells that are undergoing DNA synthesis (S-phase) and, under certain circumstances, blocks the progression of cells at the junction of the G1/S phase boundary. In vitro, the cytotoxic effect of gemcitabine is dependent on both concentration and time.

Antitumor activity in preclinical models

In animal tumour models, the anti-tumour activity of gemcitabine is schedule-dependent. When gemcitabine is administered daily, high mortality but minimal antitumour activity is observed. among animals. However if, gemcitabine is given every third or fourth day, it can be administered in non-lethal doses with substantial antitumour activity in a large number of mouse tumours.

Mechanism of action

Cellular metabolism and mechanism of action: Gemcitabine (dFdC), which is a pyrimidine antimetabolite, is metabolised intracellularly by nucleoside kinase to active difluorodeoxycytidine diphosphate (dFdCDP) and difluorodeoxycytidine triphosphate (dFdCTP). The cytotoxic effect of gemcitabine is due to inhibition of DNA synthesis by the dual mechanism of action of dFdCDP and dFdCTP. First, dFdCDP inhibits ribonucleotide reductase, which is solely responsible for catalysing the reactions that produce deoxynucleoside triphosphates (dCTP) for DNA synthesis. Inhibition of this enzyme by dFdCDP results in reduced concentration of deoxynucleosides in general and, dCTP in particular,. Second, dFdCTP competes with dCTP for incorporation into DNA (self-potentiation).

In the same way, a small quantity of gemcitabine can also be incorporated into RNA. As such, the reduced intracellular concentration of dCTP potentiates the incorporation of dFdCTP into DNA. DNA polymerase epsilon lacks the ability to eliminate gemcitabine and to repair formingDNA strands. After gemcitabine is incorporated into DNA, one additional nucleotide is added to the growing DNA strands. After this addition there is primarily a complete inhibition of further DNA synthesis (masked chain termination). After incorporation into DNA, gemcitabine appears to induce the programmed cell death process known as apoptosis.

Clinical particulars

Bladder cancer

A randomised phase III study of 405 patients with advanced or metastatic urothelial transitional cell carcinoma showed no difference between the two treatment arms, gemcitabine/cisplatin versus methotrexate/vinblastine/adriamycin/cisplatin (MVAC), in terms of median survival (12.8 and 14.8 months respectively, p=0.547), time to disease progression (7.4 and 7.6 months respectively, p=0.842) and response rate (49.4% and 45.7% respectively, p=0.512). However, the combination of gemcitabine and cisplatin had a better toxicity profile than MVAC.

Pancreatic cancer

In a randomised phase III study of 126 patients with advanced or metastatic pancreatic cancer, gemcitabine showed a statistically significant higher clinical benefit response rate than 5-fluorouracil (23.8% and 4.8% respectively, p=0.0022). Also, a statistically significant increase in the time to progression from 0.9 to 2.3 months (log-rank p<0.0002) and a statistically significant increase in median survival from 4.4 to 5.7 months (log-rank p<0.0024) was observed in patients treated with gemcitabine compared with patients treated with 5-fluorouracil.

Non small cell lung cancer

In a randomised phase III study of 522 patients with inoperable, locally advanced or metastatic non-small cell lung cancer (NSCLC), gemcitabine in combination with cisplatin showed a statistically significant higher response rate than cisplatin alone (31.0% and 12.0%, respectively, p<0.0001). A statistically significant increase in the time to progression, from 3.7 to 5.6 months (log-rank p<0.0012) and a statistically significant increase in median survival from 7.6 to 9.1 months (log-rank p<0.004) wereobserved in patients treated with gemcitabine/cisplatin compared with patients treated with cisplatin.

In another randomised phase III study of 135 patients with stage IIIB or IV NSCLC, a combination of gemcitabine and cisplatin showed a statistically significant higher response rate than a combination of cisplatin and etoposide (40.6% and 21.2%, respectively, p=0.025). A statistically significant increase in the time to progression, from 4.3 to 6.9 months (p=0.014) was observed in patients treated with gemcitabine/cisplatin compared with patients treated with etoposide/cisplatin.

In both studies similar tolerance was observed in both treatment arms.

Ovarian carcinoma

In a randomised phase III study, 356 patients with advanced epithelial ovarian carcinoma who had relapsed at least 6 months after completing platinum based therapy were randomised to therapy with gemcitabine and carboplatin (GCb), or carboplatin (Cb). A statistically significant increase in the time disease to progression, from 5.8 to 8.6 months (log-rank p= 0.0038) was observed in patients treated with GCb compared withpatients treated with Cb. Differences in terms of response rate which was 47.2% in the GCb arm versus 30.9% in the Cb arm (p=0.0016) and in median survival, which was 18 months (GCb) versus 17.3 (Cb) (p=0.73) favoured the GCb arm.

Breast cancer

In a randomised phase III study of 529 patients with inoperable, locally recurrent or metastatic breast cancer after adjuvant/neoadjuvant chemotherapy, gemcitabine in combination with paclitaxel showed a statistically significant increase intime to disease progression from 3.98 to 6.14 months (log-rank p=0.0002) in patients treated with gemcitabine/paclitaxel compared withpatients treated with paclitaxel. After 377 deaths, the overall survival was 18.6 months versus 15.8 months (log rank p=0.0489, HR 0.82) in patients treated with gemcitabine/paclitaxel compared withpatients treated with paclitaxel and the overall response rate was 41.4% and 26.2% respectively (p= 0.0002).

5.2 Pharmacokinetic properties

The pharmacokinetics of gemcitabine have been examined in 353 patients in seven studies. The 121 women and 232 men aged29 to 79 years. Of these patients, approximately 45% had non-small cell lung cancer and 35% were diagnosed with pancreatic cancer. The following pharmacokinetic parameters were obtained for doses ranging from 500 to 2,592 mg/m² that were infused from 0.4 to 1.2 hours.

Peak plasma concentrations (obtained in 5 minutes of the end of the infusion) were 3.2 to

45.5 μg/ml. Plasma concentrations of gemcitabine following a dose of 1,000 mg/m²/30-minutes were higher than 5 μg/ml for almost 30-minutes after the end of the infusion, and above0.4 μg/ml for the followinghour.

Distribution

The volume of distribution of the central compartment was 12.4 l/m² for women and 17.5 l/m² for men (the inter-individual variability was 91.9%). The volume of distribution of the peripheral compartment was 47.4 L/m². The volume of the peripheral compartment did not vary depending on sex. Plasma protein binding was considered to be negligible.

The half-life was .

between42 and 94 minutes depending on age and sex. For the recommended dosing regimen, elimination of gemcitabine should be virtually complete in 5 to 11 hours following the start of infusion. Gemcitabine does not accumulate when administered once weekly.

Biotransformation

Gemcitabine is rapidly metabolised by cytidine deaminase in the liver, kidneys, blood and other tissues. Intracellular metabolism of gemcitabine produces the gemcitabine mono, di and triphosphates (dFdCMP, dFdCDP and dFdCTP) of which dFdCDP and dFdCTP are considered active. These intracellular metabolites have not been detected in plasma or urine. The primary metabolite, 2'-deoxy-2', 2'-difluorouridine (dFdU), is not active and is found in plasma and urine.

EleminationExcretion

Systemic clearance is between 29.2 l/hr/m² and 92.2 /hr/m² depending on gender and age (inter-individual variability was 52.2%). Inwomen, clearance is approximately 25% lower than the values in men. Although rapid, it seems that, in men and women , clearance decreases with age. For the recommended dose of 1000 mg/m² as administered in a 30-minute intravenous infusion, lower clearance values in men and women do not require a gemcitabine dose reduction.

Urinary excretion: Shows that less than 10% of the drug is excreted in itsunchanged form.

Renal clearance is 2 to 7 L/h/m².

In the week following administration, 92 to 98% of the gemcitabine dose administered is recovered, 99% in the urine, primarily in the form of dFdU and 1% is eliminatedin the faeces.

dFdCTP kinetics

This metabolite can be found in circulating polymorphonuclear cells and the following information below refers to these cells. Intracellular concentrations increase in line with the dose of gemcitabine doses between 35 and -350 mg/m²/30-min, which give steady state concentrations of 0.4-5 μg/ml. For plasma concentrations above 5 μg/ml, dFdCTP levels do not increase, suggesting that formation is saturable in these cells.

Half-life of terminal elimination: 0.7-12 hours.

dFdU kinetics

This metabolite can be found in circulating polymorphnuclear cells, and the following information refers to these cells. Intracellular concentrations increase in line with the dose of gemcitabine: doses between 35- and 350 mg/m2/m²/30- min give steady state concentrations of 0.4- to 5 μg/ml. For plasma concentrations of gemcitabine beyond 5 μg/mlµg/mL, dFdCTP levels do not increase, suggesting that formation is saturable in these cells.

The Peak plasma concentrations (3-15 minutes after the end of aninfusion of, 1000 mg/m²) over 30 minutes) is 28to52 μg/ml. the lowest plasma concentration after weekly administration are: 0.07to1.12 μg/ml, with no apparent accumulation. The triphasic plasma concentrations versus time curve, shows an average terminal half-life of terminal phase - 65 hours (range 33to84 hours).

Formation of dFdU from the parent compoundis 91%-98%. The mean volume of distribution the of central compartmentis 18 L/m² (range 11to22 l/m²).

The mean steady state volume of distribution (Vss)is 150 L/m² (range 96to228 l/m²).

Tissue distribution: is significant.

Mean apparent clearanceis 2.5 L/h/m² (range 1-4 L//m²). Excretion is entirely via the urine

Gemcitabine and paclitaxel combination therapy

Combination therapy did not alter the pharmacokinetics of either gemcitabine or paclitaxel.

Gemcitabine and carboplatin combination therapy

When given in combination with carboplatin the pharmacokinetics of gemcitabine was not altered

Renal impairment

Mild to moderate renal impairment (creatinine clearance between 30 ml/min to 80 ml/min) has no consistent, significant effect on the pharmacokinetic properties of gemcitabine

5.3 Preclinical safety data

In repeat-dose studies for up to 6 months in performed in mice and dogs, the main observation was proragmmed and dose-dependent suppression of haematopoiesis, the effects of which werereversible.

has demonstrated is mutagenic effects in an in vitro mutation test and in an in vivo bone marrow micronucleus test. Long term animal studies assessing the carcinogenic potential have not been conducted.

In fertility studies, gemcitabine caused reversible hypospermatogenesis in male mice. No effects on female fertility weredetected.

Assessment of experimental animal studies has shown reproductive toxicity e.g. for example congenital abnormalities and other effects on the development pregnancy progression and or peri- and post-natal development.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Gemcitabine 2 g powder for solution for infusion contains: Mannitol (E421)

Sodium acetate (E262)

Hydrochloric acid (E507) (for pH adjustment)

Sodium hydroxide (E524) (for pH adjustment)

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf life

As packaged for sale:

3 years

After reconstitution: Chemical and physical in-use stability has been demonstrated for 21 days at 25°C. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 25°C, unless reconstitution (and further dilution, if applicable) has taken place in controlled and validated aseptic conditions.

Solutions of reconstituted gemcitabine should not be refrigerated, as crystallisation may occur.

6.4 Special precautions for storage

As packaged for sale:

This medicinal product does not require any special storage conditions.

In-use:

For storage condition of the reconstituted medicinal product, see section 6.3.

6.5 Nature and contents of container

The product is contained in 100 ml Type I clear moulded glass vial and are closed with 20 mm grey bromobutyl rubber stopper and sealed with 20 mm aluminium flip off violet seal.

1 vial per pack.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Handling

The normal safety precautions for cytostatic agents must be observed when preparing and disposing of the infusion solution. Handling of the solution for infusion should be done in a safety box and protective coats and gloves should be used. If no safety box is available, the equipment should be supplemented with a mask and protective glasses.

If the preparation comes into contact with the eyes, this may cause serious irritation. The eyes should be rinsed immediately and thoroughly with water. If there is lasting irritation, a doctor should be consulted. If the solution is spilled on the skin, rinse thoroughly with water.

Instructions for reconstitution (and further dilution, if performed) The only approved diluent for reconstitution of gemcitabine sterile powder is sodium chloride 9 mg/mL (0.9%) solution for injection (without preservative). Due to solubility considerations, the maximum concentration for gemcitabine upon reconstitution is 40 mg/ml. Reconstitution at concentrations greater than 40 mg/ml may result in incomplete dissolution and should be avoided.

1. 1. Use aseptic technique during the reconstitution and any further dilution of gemcitabine for intravenous infusion administration.
2. 2.

   To reconstitute, add 50 ml of sterile sodium chloride 9 mg/ml (0.9 %)

   solution for injection, without preservative. The total volume after reconstitution is 52.6 ml. This yields a gemcitabine concentration of 38 mg/ml, which includes accounting for the displacement volume of the lyophilised powder. Shake to dissolve. Further dilution with sterile sodium chloride 9 mg/ml (0.9 %) solution for injection, without preservative can be done. Reconstituted solution is a clear colourless to light straw-coloured solution.

3. 3. Parenteral medicinal products should be inspected visually for particulate matter and discolouration prior to administration. If particulate matter is observed, do not administer.

Any unused product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Accord Healthcare Limited,

Sage House,

319, Pinner Road,

North Harrow,

Middlesex,

HA1 4HF,

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 20075/0262

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

13/07/2011

10 DATE OF REVISION OF THE TEXT

26/01/2024