Gemcitabine 200 Mg/1 G Solution

GEMCITABINE OETHMAAN is indicated for treatment in patients:

• with non-small cell lung cancer that is either locally advanced or metastatic.
• with locally advanced (non-resectable Stage II or Stage III) or metastatic (Stage IV) adenocarcinoma of the pancreas.
• with transitional cell bladder cancer.
• with unresectable, locally recurrent or metastatic breast cancer due to relapse following adjuvant/neoadjuvant chemotherapy. Treatment usually in combination with paclitaxel. Prior chemotherapy should have included an anthracycline unless clinically contraindicated.
• alone or in combination, for the treatment of patients with recurrent epithelial ovarian carcinoma who have relapsed following platinum-based chemotherapy.

Posology

Non-small cell lung cancer:

Adults: The recommended monochemotherapy dosage is 1 000 mg/m2, given as a 30 minute intravenous infusion. This treatment should be repeated once weekly for three weeks, followed by a one week rest period. This four week cycle is then repeated. Dosage reduction with each cycle or within a cycle may be useful based upon the amount of toxicity experienced by the patient.

GEMCITABINE OETHMAAN may be used concomitantly with cisplatin using either a three or four week schedule. One of the following schedules is suggested:

3 week schedule: 1 250 mg/m2 GEMCITABINE OETHMAAN given as a 30 minute intravenous infusion on the 1st and 8th day of every 21 day cycle and 100 mg/m2 cisplatin administered on the 1st day. Dosage reduction with each cycle or within a cycle may be useful based upon the amount of toxicity experienced by the patient.

4 week schedule: 1 000 mg/m2 GEMCITABINE OETHMAAN given as a 30 minute intravenous infusion on the 1st, 8th and 15th day of every 28 day cycle and 100 mg/m2 cisplatin administered on either the 1st, 2nd or 15th day. Dosage reduction with each cycle or within a cycle may be useful based upon the amount of toxicity experienced by the patient.

Pancreatic cancer:

Adults: The recommended dose of GEMCITABINE OETHMAAN is 1 000 mg/m2 given as a 30 minute intravenous infusion. This should be repeated once weekly for up to 7 weeks followed by 1 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 useful based upon the amount of toxicity experienced by the patient.

Bladder cancer:

Adults: The recommended monochemotherapy dosage of GEMCITABINE OETHMAAN is 1 250 mg/m2 given as a 30 minute intravenous infusion. The dose should be given on the 1st, 8th and 15th day of each 28 day cycle. This four week cycle is then repeated. Dosage reduction with each cycle or within a cycle may be useful based upon the amount of toxicity experienced by the patient.

GEMCITABINE OETHMAAN may be used concomitantly with cisplatin. The recommended dose of GEMCITABINE OETHMAAN is 1 000 mg/m2 given as a 30 minute infusion. The dose should be given on the 1st, 8th and 15th day of each 28 day cycle in combination with cisplatin. Cisplatin is given at a recommended dose of 70 mg/m2 on the 1st day concomitantly with GEMCITABINE OETHMAAN or on the 2nd day of each 28 day cycle. This four week cycle is then repeated. Dosage reduction with each cycle or within a cycle may be useful based upon the amount of toxicity experienced by the patient.

Breast cancer:

Adults: For treatment of breast cancer, recommended treatment is GEMCITABINE OETHMAAN in combination with paclitaxel. 175 mg/m2 paclitaxel administered on the 1st day over approximately 3 hours as a intravenous infusion, followed by 1 250 mg/m2 GEMCITABINE OETHMAAN as a 30 minute intravenous infusion on the 1st and 8th day of the 21 day cycle. Dose reduction with each cycle or within a cycle may be useful based upon the amount 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 OETHMAAN and paclitaxel combination.

Ovarian Cancer:

Single medicine use:

Adults: The recommended dose of GEMCITABINE OETHMAAN is 800 to 1 250 mg/m2, given by a 30 minute intravenous infusion. The dose should be given on days 1, 8 and 15 of each 28 day cycle. This four week cycle is then repeated. Dosage reduction with each cycle or within a cycle may be applied based upon the amount of toxicity experienced by the patient.

Combination use:

Adults: GEMCITABINE OETHMAAN in combination with carboplatin is recommended using GEMCITABINE OETHMAAN 1 000 mg/m2 administered on days 1 and 8 of each 21 day cycle as a 30 minute intravenous infusion. After GEMCITABINE OETHMAAN, carboplatin will be given on day 1 consistent with a target AUC of 4,0 g/ml/min. Dosage reduction with each cycle or within a cycle may be applied based upon the amount of toxicity experienced by the patient.

Patients receiving GEMCITABINE OETHMAAN should be monitored prior to each dose for platelet, leucocyte and granulocyte counts and if necessary, the dose of GEMCITABINE OETHMAAN may be either reduced or withheld in the presence of haematological toxicity according to the following scale:

Absolute granulocyte Count (x 106/L) Platelet count (x 106/L) % of full dose

> 1 000 and 500 u2013 1000 or < 500 or > 100 000 50 000 u2013 100 000 < 50 000 100 75 hold

Periodic physical examination and checks of renal and hepatic function should be made to detect non-haematologic toxicity. Dosage reduction with the cycle or within a cycle may be useful based upon the amount of toxicity experienced by the patient. Doses should be withheld until toxicity has resolved in the opinion of the medical practitioner.

Special Populations

Patients with hepatic or renal impairment: GEMCITABINE OETHMAAN should be used with caution in patients with hepatic insufficiency or with impaired renal function as no studies have been done in patients with significant renal or hepatic impairment. There is insufficient information from clinical studies to allow clear dose recommendation for this patient population. Periodic physical examination and checks of renal and hepatic function should be made to detect non-haematologic toxicity. Dosage reduction with each cycle or within a cycle may be applied based upon the amount of toxicity experienced by the patient. Doses should be withheld until toxicity has resolved in the opinion of the medical practitioner.

Elderly patients: GEMCITABINE OETHMAAN has been well tolerated in patients over the age of 65. There is no evidence to suggest that dose adjustments are necessary in the elderly, although gemcitabine clearance and half-life are affected by age.

Method of administration

GEMCITABINE OETHMAAN is for use as intravenous infusion only. GEMCITABINE OETHMAAN is well tolerated during infusion, with only a few reported cases of reaction at the injection site. There have been no reports of necrosis at the injection site. GEMCITABINE OETHMAAN can be easily administered on an outpatient basis. Information on instructions for preparation and reconstitution, see section 6.6.

GEMCITABINE OETHMAAN is contraindicated in:

• patients with known hypersensitivity to gemcitabine or to any of the excipients of GEMCITABINE OETHMAAN listed in section 6.1.
• Pregnancy and lactation (see section 4.6). The safety of GEMCITABINE OETHMAAN in human pregnancy and lactation has not been established.
• Usage in children: Safety and effectiveness in children have not been established.

Toxicity has been known to increase should there be prolongation of infusion time and increased dosing frequency. GEMCITABINE OETHMAAN can suppress bone marrow function as manifested by leucopoenia, thrombocytopenia and anaemia. GEMCITABINE OETHMAAN can cause myelosuppression which is usually mild to moderate and is more pronounced in granulocyte count. Peripheral blood counts may continue to deteriorate after GEMCITABINE OETHMAAN administration has been stopped. In patients with impaired bone marrow function, the treatment should be started with caution. The risk of cumulative bone-marrow suppression must be considered when GEMCITABINE OETHMAAN treatment is given together with other chemotherapy medicines. Hepatic insufficiency administration of GEMCITABINE OETHMAAN 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 OETHMAAN 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). GEMCITABINE OETHMAAN has radiosensitising activity.

Concomitant radiotherapy: Concomitant radiotherapy (given together or u2264 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).

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 (CLS): Capillary leak syndrome has been reported in patients receiving GEMCITABINE OETHMAAN as single medicine or in combination with chemotherapeutic medicines. 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 OETHMAAN 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.

Posterior reversible encephalopathy syndrome (PRES): Reports of posterior reversible encephalopathy syndrome (PRES) with potentially severe consequences have been reported in patients receiving GEMCITABINE OETHMAAN as single medicine or in combination with other chemotherapeutic medicines. 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 OETHMAAN should be permanently discontinued and supportive measures implemented, including blood pressure control and antiseizure therapy, if PRES develops during therapy.

Pulmonary toxicity: Treatment should be stopped if interstitial pneumonitis together with pulmonary infiltrates should occur. Steroids may result in some relief. Treatment should cease if severe pulmonary effects, such as pulmonary oedema, interstitial pneumonitis and adult respiratory distress syndrome should occur. Early stage supportive treatment may improve the situation.

Renal toxicity: Haemolytic uraemic syndrome. Use with caution in patients with impaired renal function. Clinical findings consistent with the haemolytic uraemic syndrome (HUS) were rarely reported in patients receiving gemcitabine (see section 4.8). Discontinue GEMCITABINE OETHMAAN at first signs 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 even with discontinuation of therapy and dialysis may be required.

General: Patients receiving therapy with GEMCITABINE OETHMAAN must be closely monitored. Evaluation of renal and hepatic function as well as medicine toxicity is required. Carcinogenesis, mutagenesis, impairment of fertility: Cytogenic damage has been produced by gemcitabine in an in vivo assay. Gemcitabine induced forward mutation in vitro in a mouse lymphoma assay. The influence of GEMCITABINE OETHMAAN on fertility has not been established in humans.

Fertility: In fertility studies gemcitabine caused hypospermatogenesis in male mice. Therefore, men being treated with gemcitabine are advised not to father a child during and up to 3 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).

Severe cutaneous adverse reactions (SCARs): 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 OETHMAAN should be withdrawn immediately.

Sodium: After reconstitution, GEMCITABINE 200 mg OETHMAAN and GEMCITABINE 1 g OETHMAAN contain 17,7 mg and 88,5 mg sodium per vial, equivalent to 0,9 % and 4,43 % of the WHO maximum daily intake (RDI) of 2 g sodium for and adult, respectively.

Radiotherapy: CONCURRENT (GIVEN TOGETHER OR u2264 7 DAYS APART)- TOXICITY ASSOCIATED WITH THIS MULTIMODALITY THERAPY IS DEPENDENT ON MANY DIFFERENT FACTORS, INCLUDING DOSE OF GEMCITABINE OETHMAAN, FREQUENCY OF GEMCITABINE OETHMAAN ADMINISTRATION, DOSE OF RADIATION, RADIOTHERAPY PLANNING TECHNIQUE, THE TARGET TISSUE, AND TARGET VOLUME. PRE-CLINICAL AND CLINICAL STUDIES HAVE SHOWN THAT GEMCITABINE HAS RADIOSENSITIZING ACTIVITY. IN A SINGLE TRIAL, WHEN 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 ESOPHAGITIS, AND PNEUMONITIS WAS OBSERVED, PARTICULARLY IN PATIENTS RECEIVING LARGE VOLUMES OF RADIOTHERAPY (MEDIAN TREATMENT VOLUMES 4 795 cm3). THE OPTIMUM REGIMEN FOR SAFE ADMINISTRATION OF GEMCITABINE OETHMAAN WITH THERAPEUTIC DOSES OF RADIATION HAS NOT YET BEEN DETERMINED IN ALL TUMOUR TYPES. RADIATION INJURY HAS BEEN REPORTED ON TARGETED TISSUES (e.g. ESOPHAGITIS, COLITIS, AND PNEUMONITIS) IN ASSOCIATION WITH BOTH CONCURRENT AND NONCONCURRENT USE OF GEMCITABINE OETHMAAN.

Other: Yellow fever and other live attenuated vaccines are not recommended due to the risk of systemic, possibly fatal, disease, particularly in immunosuppressed patients.

Safety in pregnancy and lactation has not been established.

Women of childbearing age/contraception in men and women: Due to the genotoxic potential of gemcitabine, women of childbearing age must use effective 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.

Breastfeeding: 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. Therefore, men being treated with gemcitabine are advised not to father a child during and up to 3 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.

GEMCITABINE OETHMAAN can result in mild to moderate somnolence. Use with caution when driving or operating machinery until it is established that the patient does not become somnolent.

a. Summary of the safety profile

The most frequently 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 10-40 % 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).

b. Tabulated list of adverse reactions

System Organ Class Adverse reaction Frequency Infections and infestations Infections Frequent Sepsis Frequency unknown Blood and lymphatic system disorders Leucopenia, thrombocytopenia, anaemia. Myelosuppression is usually transient and usually does not result in dose reduction and rarely results in discontinuation. Dosage reduction or omission may be necessary in severe bone marrow depression cases. Febrile neutropenia Frequent Thrombocytosis, Thrombotic microangiopathy Less frequent Immune system disorders Anaphylactoid reaction Less frequent Metabolism and nutrition disorders Anorexia Frequent Nervous system disorders Headache, somnolence, insomnia Frequent Cerebrovascular accident, Posterior reversible encephalopathy syndrome Less frequent Cardiac disorders Myocardial infarct, heart failure, dysrrhythmia (predominantly supraventricular in nature). Less frequent Vascular disorders Clinical signs of peripheral vasculitis, gangrene, hypotension, capillary leak syndrome Less frequent Respiratory, thoracic and mediastinal disorders Dyspnoea Cough and rhinitis Frequent Bronchospasm, pulmonary oedema, interstitial pneumonitis (with associated pulmonary infiltrates), adult respiratory distress syndrome. Less frequent Gastrointestinal disorders Nausea, vomiting Diarrhoea, stomatitis and ulceration of the mouth, constipation. Frequent Ischaemic colitis Less frequent Hepatobiliary disorders Elevation of liver transaminases (AST and ALT) and alkaline phosphatases; Increased bilirubin Frequent Serious hepatotoxicity including liver failure and death, increased gamma-glutamyl transferase (GGT) Less frequent Skin and subcutaneous tissue disorders Allergic skin rash frequently associated with pruritis, alopecia Frequent Severe skin reactions including desquamation and bullous skin eruptions, ulceration, vesicle and sore formation, scaling, toxic epidermal necrolysis, Steven-Johnson syndrome, pseudocellulitis, AGEP u2013 acute generalized exanthematous pustulosis (see section 4.4), Lyell's Syndrome Frequency unknown Musculoskeletal and connective tissue disorders Back pain, myalgia Frequent Renal and urinary disorders Haematuria, mild proteinuria Frequent Renal failure, haemolytic uraemic syndrome Less frequent General disorders and administration site conditions 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. Fever, asthenia, chills Frequent Injection site reaction mainly mild in nature Less frequent Investigations Elevation of liver transaminase and alkaline phosphatase Frequent Injury, poisoning and procedural complications Radiosensitisation and radiation recall Less frequent 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.

In the event of an overdose, the patient should be monitored with appropriate blood counts and supportive treatment should be administered, as necessary. There is no known antidote for the overdosage of GEMCITABINE OETHMAAN.