Gembicen 200 mg/1000 mg/2000 mg Solution

GEMBICEN is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer. GEMBICEN is indicated as first-line treatment for patients with locally advanced (non-resectable Stage II or Stage III) or metastatic (Stage IV) adenocarcinoma of the pancreas. GEMBICEN is indicated for patients previously treated with 5-FU (fluorouracil). GEMBICEN is indicated for treatment of patients with transitional cell bladder cancer. GEMBICEN, 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. GEMBICEN, alone or in combination, is indicated for the treatment of patients with recurrent epithelial ovarian carcinoma who have relapsed following platinum-based chemotherapy.

Posology:
Patients with hepatic or renal impairment
GEMBICEN 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.

Non-small cell lung cancer
Adults: The recommended mono-chemotherapy dosage is 1 000 mg/mu00b2, given by 30 minute intravenous infusion. This 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 applied based upon the amount of toxicity experienced by the patient.

GEMBICEN may be used in combination with cisplatin using either a three-week or a four-week schedule. One of the following regimens is suggested:
3-week schedule: GEMBICEN 1 250 mg/mu00b2, given by 30-minute intravenous infusion on days 1 and 8 of every 21 day cycle and cisplatin 100 mg/mu00b2 on day 1. Dosage reduction with each cycle or within a cycle may be applied based upon the amount of toxicity experienced by the patient.
4 week schedule: GEMBICEN 1 000 mg/mu00b2 on days 1, 8 and 15 of every 28 day cycle and cisplatin 100 mg/mu00b2 on either day 1, 2 or 15 of therapy. Dose reduction with each cycle or within a cycle may be applied based upon the amount of toxicity experienced by the patient.

Pancreatic cancer
Adults: The recommended dose of GEMBICEN is 1 000 mg/mu00b2, 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 amount of toxicity experienced by the patient.

Bladder cancer
Adults: The recommended monochemotherapy dosage of GEMBICEN is 1 250 mg/mu00b2, given by 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.

GEMBICEN may be used in combination with cisplatin. The recommended dose of GEMBICEN is 1 000 mg/mu00b2, 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/mu00b2 on day 1 following GEMBICEN or day 2 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. A clinical trial showed more myelosuppression when cisplatin was used in doses of 100 mg/mu00b2.

Breast cancer
Adults: GEMBICEN in combination with paclitaxel is recommended using paclitaxel (175 mg/mu00b2) administered on day 1 over approximately 3 hours as an intravenous infusion, followed by GEMBICEN (1 250 mg/mu00b2) 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 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 GEMBICEN and paclitaxel combination.

Ovarian cancer
Single medicine use in adults: The recommended dose of GEMBICEN is 800 to 1 250 mg/mu00b2, 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 in adults: GEMBICEN in combination with carboplatin is recommended using GEMBICEN 1 000 mg/mu00b2 administered on days 1 and 8 of each 21 day cycle as a 30 minute intravenous infusion. After GEMBICEN, carboplatin will be given on day 1 consistent with a target area under the curve (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 GEMBICEN should be monitored prior to each dose for platelet, leucocyte and granulocyte counts and, if necessary, the dose of GEMBICEN may be either reduced or withheld in the presence of haematological toxicity, according to the following scale:

Table 2:
Absolute granulocyte count (x 106/L) Platelet count (x 106/L) Percentage of full dose (%)
> 1 000 and > 100 000 100
500 u2013 1 000 or 50 000 u2013 100 000 75
< 500 or < 50 000 hold

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. GEMBICEN is well tolerated during the infusion, with only a few cases of injection site reaction reported. GEMBICEN can be easily administered on an outpatient basis.

Special populations
Elderly patients: GEMBICEN 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 GEMBICEN clearance and half-life are affected by age.
Paediatric population: Safety and effectiveness in children have not been established.

Method of administration:
GEMBICEN is for intravenous use only. GEMBICEN is administered as a 30 minute intravenous infusion. For instructions on dilution of the medicine before administration, see section 6.6.

Patients with known hypersensitivity to gemcitabine or to any of the excipients listed in section 6.1. Pregnancy and breastfeeding: The safety of gemcitabine in human pregnancy and lactation has not been established. Usage in children: Safety and effectiveness in children have not been established.

Prolongation of the infusion time and increased dosing frequency have been shown to increase toxicity.
Haematological toxicity
GEMBICEN can suppress bone marrow function as manifested by leucopenia, thrombocytopenia and anaemia. Myelosuppression is usually mild to moderate and is more pronounced for the granulocyte count (see section 4.2 & 4.8). Patients receiving GEMBICEN should be monitored prior to each dose for platelet, leucocyte and granulocyte counts. Suspension or modification of therapy should be considered when medicine-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 GEMBICEN 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 GEMBICEN treatment is given together with other chemotherapy.

Hepatic and renal impairment
GEMBICEN should be used with caution in patients with hepatic impairment 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). Administration of GEMBICEN 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 u2264 7 days apart): Toxicity has been reported (see section 4.5).

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

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

Cardiovascular
Due to the risk of cardiac and/or vascular disorders with GEMBICEN, 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 treatment or in combination with other chemotherapeutic treatments (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. GEMBICEN 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 GEMBICEN 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 less frequently reported (post-marketing data) in patients receiving gemcitabine (see section 4.8). HUS is a potentially life-threatening disorder. 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.

GEMBICEN contains sodium. This medicine contains less than 1 mmol sodium (23 mg) per unit volume, that is to say it is essentially sodium free.

No specific interaction studies have been performed (see section 5.2).
Radiotherapy
Concurrent (given together or u2264 7 days apart) u2013 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/mu00b2 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 cmu00b3). 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/mu00b2, four times) and cisplatin (80 mg/mu00b2 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) u2013 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 suggests 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, as in GEMBICEN.
Others
Yellow fever and other live attenuated vaccines are not recommended due to the risk of systemic, possibly fatal, disease, particularly in immunosuppressed patients.

Pregnancy
There are no adequate data from the use of GEMBICEN in pregnant women. Studies in animals have shown reproductive toxicity. Based on results from animal studies and the mechanism of action of gemcitabine, GEMBICEN should not be used during pregnancy (see section 4.3). Women should be advised not to become pregnant during treatment with GEMBICEN and to warn their attending medical practitioner immediately, should this occur after all.
Breastfeeding
It is not known whether gemcitabine is excreted in human milk and adverse effects on the suckling child cannot be excluded. Breastfeeding must be discontinued during GEMBICEN therapy (see section 4.3).
Fertility
In fertility studies gemcitabine caused hypospermatogenesis in male mice. Therefore, men being treated with GEMBICEN 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 GEMBICEN.

No studies on the effects on the ability to drive and use machines have been performed. However, GEMBICEN can 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.

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, proteinuria and haematuria, dyspnoea (highest incidence in lung cancer patients), allergic skin rashes which is associated with itching in some 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).

Tabulated summary of adverse reactions
SYSTEM ORGAN CLASS FREQUENCY ADVERSE REACTIONS
Infections and infestations Frequent Infections.
Frequency unknown Sepsis.
Blood and lymphatic system disorders Frequent 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 & 4.4), thrombocytopenia, anaemia, febrile neutropenia. Dosage reduction or omission may be necessary for severe bone marrow depression (see section 4.2).
Less frequent Thrombocytosis, thrombotic microangiopathy.
Immune system disorders Less frequent Anaphylactoid reaction.
Metabolism and nutrition disorders Frequent Anorexia
Nervous system disorders Frequent Headache, insomnia, somnolence
Less frequent Cerebrovascular accident, posterior reversible encephalopathy syndrome (see section 4.4).
Cardiac disorders Less frequent Dysrhythmias (predominantly supraventricular in nature), heart failure, myocardial infarction
Vascular disorders Less frequent Clinical signs of peripheral vasculitis and gangrene, hypotension, capillary leak syndrome (see section 4.4).
Respiratory, thoracic and mediastinal disorders Frequent Dyspnoea u2013 usually mild and passes rapidly without treatment, cough, rhinitis.
Less frequent Interstitial pneumonitis (see section 4.4), bronchospasm u2013 usually mild and transient but may require parenteral treatment, pulmonary oedema, adult respiratory distress syndrome (see section 4.4). Frequency unknown Pulmonary eosinophilia.
Gastrointestinal disorders Frequent Vomiting, nausea, diarrhoea, stomatitis and ulceration of the mouth, constipation.
Less frequent Ischaemic colitis.
Hepatobiliary disorders Frequent Elevation of liver transaminases (AST and ALT) and alkaline phosphatase, increased bilirubin.
Less frequent Serious hepatotoxicity including liver failure and death, increased gamma-glutamyl transferase (GGT).
Skin and subcutaneous tissue disorders Frequent Allergic skin rash frequently associated with pruritus, alopecia, itching, sweating.
Less frequent Severe skin reactions, including desquamation and bullous skin eruptions, ulceration, vesicle and sore formation, scaling, toxic epidermal necrolysis, Stevens-Johnson syndrome. Frequency unknown Pseudocellulitis.
Musculoskeletal and connective tissue disorders Frequent Back pain, myalgia.
Renal and urinary disorders Frequent Haematuria, mild proteinuria.
Less frequent Renal failure (see section 4.4), haemolytic uraemic syndrome (see section 4.4).
General disorders and administration site conditions Frequent 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.
Less frequent Injection site reactions u2013 mainly mild in nature.
Injury, poisoning and procedural complications Less frequent Radiation toxicity (see section 4.5), radiation recall.

Description of selected adverse reactions
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.
Oedema
Oedema is usually reversible after stopping treatment. The mechanism of the toxicity is unknown. It is not associated with any evidence of cardiac, hepatic or renal failure.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of GEMBICEN is important. It allows continued monitoring of the benefit/risk balance of GEMBICEN. Health care providers are requested to report any suspected adverse reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website.

There is no known antidote for overdose of gemcitabine. In the event of suspected overdose, the patient should be monitored with appropriate blood counts and receive supportive therapy, as necessary.