Gemcitabin Hexal IV Infusion

Gemcitabine (dFdC) is metabolised intracellularly by nucleoside kinases to the active diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides. The cytotoxic action of Gemcitabine appears to be due to inhibition of DNA synthesis by two actions of dFdCDP and dFdCTP. First, dFdCDP inhibits ribonucleotide reductase which is uniquely responsible for catalysing the reactions that generate the deoxynucleoside triphosphates for DNA synthesis. Inhibition of this enzyme by dFdCDP causes a reduction in the concentrations of deoxynucleosides in general, and especially in that of dCTP. Secondly, dFdCTP competes with dCTP for incorporation into DNA. Likewise, a small amount of Gemcitabine may also be incorporated into RNA. Thus, the reduction in the intracellular concentration of dCTP potentiates the incorporation of dFdCTP into DNA (self-potentiation). DNA polymerase epsilon is essentially unable to remove Gemcitabine and repair the growing DNA strands. After Gemcitabine is incorporated into DNA, one additional nucleotide is added to the growing DNA strands. After this addition, there is essentially a complete inhibition in further DNA synthesis (masked chain termination). After incorporation into DNA, Gemcitabine then appears to induce the programmed cellular death process known as apoptosis.

Non-Small Cell Lung Cancer:

• Single-agent Use: The recommended dose of Gemcitabine is 1000 mg/m2, 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.
• Combination Use: Gemcitabine, in combination with Cisplatin has been investigated using two dosing regimens. One regimen used a three-week schedule and the over used a four-week schedule. The three-week schedule used Gemcitabine 1250 mg/m2, given by 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 applied based upon the amount of toxicity experienced by the patient. The four-week schedule used Gemcitabine 1000 mg/m2, given by 30-minute intravenous infusion, on days 1,8, and 15 of each 28-day cycle. Dosage reduction with each cycle or within a cycle may be applied based upon the amount of toxicity experienced by the patient.

Pancreatic Cancer: The recommended dose of Gemcitabine is 1000 mg/m2, given by 30-minute intravenous infusion. This should be repeated once weekly for up to 7 weeks followed by a week of rest. Subsequent cycles should consist of injections once weekly for 3 consecutive weeks out of every 4 weeks. Dosage reduction with each cycle or within a cycle may be applied based upon the amount of toxicity experienced by the patient.

Bladder Cancer:

• Single agent use: The recommended dose of Gemcitabine is 1250 mg/m2, given by 30-minute intravenous infusion. The dose should be given on days 1,8 and 15 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 amount of toxicity experienced by the patient.
• Combination use: The recommended dose for Gemcitabine is 1000 mg/m2, given by 30-minute infusion, The dose should be given on days 1,8 and 15 of each 28-day cycle in combination with Cisplatin. Cisplatin is given at a recommended dose of 70 mg/m2 on day 1 following Gemcitabine or day 2 of each 28-day cycle. This 4-week cycle is then repeated. Dosage reduction with each cycle or within a cycle may be applied based upon the amount of toxicity experienced by the patient. A clinical trial showed more myelosuppression when Cisplatin was used in doses of 100 mg/m2.

Breast Cancer: Gemcitabine in combination with Paclitaxel is recommended using Paclitaxel (175 mg/m2) administered on Day 1 over approximately 3 hours as an intravenous infusion, followed by Gemcitabine (1250 mg/m2) as a 30-minute intravenous infusion on Days 1 and 8 of each 21-day cycle. Dose reduction with each cycle or within a cycle may be applied based upon the amount of toxicity experienced by the patient. Patients should have an absolute granulocyte count of at least 1,500 (x106/L) prior to initiation of Gemcitabine + Paclitaxel combination.

Ovarian Cancer: Gemcitabine in combination with Carboplatin is recommended using Gemcitabine 1000 mg/m2 administered on days 1 and 8 of each 21-day cycle as a 30-minute intravenous infusion. After Gemcitabine, Carboplatin should be given on day 1 consistent with target AUC of 4.0 mg/mL/min. Dosage reduction with each cycle or within a cycle may be applied based upon the amount of toxicity experienced by the patient.

No confirmed interactions have been reported with the use of Gemcitabin Hexal. No specific drug interaction studies have been conducted.

It is contraindicated in patients with known hypersensitivity to Gemcitabine or any other components of this product.

Haematological Toxicity: Because Gemcitabin Hexal is a bone marrow suppressant, anaemia, leukopenia, and thrombocytopenia can occur as a result of administration of Gemcitabin Hexal. Myelosuppression is usually mild to moderate and is more pronounced for the granulocyte count. While two-thirds of patients experience some anaemia, only 7% have haemoglobin levels drop below 8 g/100 mL. While 19% of patients received transfusions, only 0.2% of patients discontinued because of anaemia. The white blood cell count is depressed in 61 % of patients, however only 9% of patients experience WBC's below 2000 cells/mm 3 and only 0.1% discontinued for leukopenia. Sixty-four percent of patients have reduced granulocyte counts and almost 25% drop below 1000 cells/mm 3 . Platelet counts are reduced in 21% of patients but only 5% of patients experience counts below 50,000 cells/mm 3 and only 0.4% of patients were discontinued due to thrombocytopenia. Previous therapy with cytotoxic agents appears to increase the frequency and severity of the leukopenia, granulocytopenia, and thrombocytopenia. There is no evidence of cumulative haematological toxicity. Anaemia is manageable with the use of conventional transfusions. Dose reduction or omission may be necessary for severe leukopenia or thrombocytopenia. Rare cases of haemorrhage occurring simultaneously with thrombocytopenia have been reported, but were usually thought to be disease-related. Thrombocythemia is also commonly reported (7.5% of patients), but no patients were discontinued for this event. Febrile neutropenia is also commonly reported.

Hepatic Toxicity: Abnormalities of liver transaminase enzymes occur in about two-thirds of patients, but they are usually mild, non- progressive, and rarely necessitate stopping treatment. Less than 10% of patients experience elevations greater than 5 times normal and only 0.5% of patients were discontinued for abnormalities in liver function. One patient was discontinued for liver failure, but the assessment was complicated by a history of chronic alcoholism. Alanine transaminase (ALT) effects decline over time despite continued treatment. Elevations of alkaline phosphatase greater than 5 times normal occurred in 6.6% of patients but may have been due to bone disorders. Bilirubin values greater than 5 times normal were observed in 1.5% of patients, but ninety percent of patients had normal bilirubin levels.

Gastrointestinal: Nausea, and nausea accompanied by vomiting are each reported in about one-third of patients, respectively. This adverse event requires therapy in about 20% of patients, is rarely dose-limiting, and is easily manageable with standard antiemetics. Only 0.9% of patients report intractable vomiting and only 0.9% of patients discontinued due to nausea and vomiting. Diarrhoea and stomatitis are commonly reported. Diarrhoea (transient to tolerable) was reported by 7% of patients. Intolerable diarrhoea requiring therapy was reported in 0.5% of patients. No patients discontinued treatment because of diarrhoea.

Genito-Urinary Toxicity: Mild proteinuria and haematuria are reported in approximately half the patients, but are rarely clinically significant, and are not usually associated with any change in serum creatinine or blood urea nitrogen. However, a few cases (0.6% of patients) of renal failure of uncertain aetiology have been reported hence Gemcitabin Hexal should be used with caution in patients with impaired renal function. Rare cases (0.4%) of possible haemolytic uraemic syndrome have been reported. Cumulative renal toxicity has not been observed.

Pulmonary Toxicity: Dyspnoea occurring within hours following Gemcitabin Hexal injection is reported by approximately 10% of patients. This dyspnoea is usually mild and short-lived, rarely dose-limiting, and usually abates spontaneously without any specific therapy. The mechanism of this toxicity is unknown and the relationship to Gemcitabin Hexal is not clear. Only 0.6% of patients discontinued due to dyspnoea and only 0.1 % of these were believed to be medicine-related. Interstitial pneumonitis has been reported infrequently.

Allergic Toxicity: A rash is seen in approximately 25% of patients and is associated with pruritus in about 10% of patients. The rash is usually mild, not dose-limiting, and responds to local therapy. Desquamation, vesiculation, and ulceration have been reported rarely. Discontinuations for cutaneous toxicity were reported for only 0.3% of patients. Gemcitabin Hexal is well tolerated during the infusion with only a few cases of injection site reaction reported. Gemcitabin Hexal does not appear to be a vesicant. There have been no reports of injection site necrosis. Bronchospasm is usually mild and transient, but parenteral therapy may be required. Gemcitabin Hexal should not be administered to patients with a known hypersensitivity to the medicine.

Neurotoxicity: Mild to moderate somnolence occurs in approximately 10% of patients. Only 0.1 % of patients discontinued for somnolence. Asthenia is frequently reported with other flu symptoms but is also reported as an isolated symptom. Asthenia was cause for discontinuation by 1.4% of patients. Paresthesias are reported in 3.4% of patients, but only 0.2% report these as severe. Oedema/Peripheral Oedema : Oedema/peripheral oedema is reported by approximately 30% of patients. Some cases of facial oedema have also been reported. Pulmonary oedema was reported infrequently (1%). Oedema/peripheral oedema is usually mild to moderate, rarely dose-limiting, is sometimes reported as painful and is usually reversible after stopping Gemcitabin Hexal treatment. The mechanism of this toxicity is unknown. However, it was not associated with any evidence of cardiac, renal or hepatic failure. Oedema resulted in the discontinuation of 0.7% of patients.

Alopecia: Overall, 86.7% of patients had no hair loss at all. Minimal to moderate hair loss was reported by 13% of patients. Only 0.5% of patients reported complete but reversible alopecia.

Pregnancy Category D. Gemcitabine should be used during pregnancy. It is not known whether Gemcitabine is excreted in human breast milk.

Caution should be exercised when using Gemcitabin Hexal in patients with the risk of Schedule-dependent Toxicity, Myelosuppression, Pulmonary Toxicity and Respiratory Failure, Hemolytic Uremic Syndrome, Hepatic Toxicity, Embryofetal Toxicity, Radiation Therapy Toxicity and Impairment of Fertility.

Elderly Patients: Gemcitabin Hexal has been well tolerated in patients over the age of 65. There is no evidence to suggest that dose adjustments, other than those recommended for all patients, are necessary in the elderly, although Gemcitabin Hexal clearance and half-life are affected by age.

Renal and Hepatic Impairment: Gemcitabin Hexal should be used with caution in patients with impaired renal function or hepatic insufficiency, as there is insufficient information from clinical studies to allow clear recommendation for this patient population. Mild to moderate renal insufficiency (GFR from 30 mL/min to 80 mL/m in) has no consistent, significant effect on Gemcitabin Hexal pharmacokinetics.

Children: Gemcitabin Hexal has been studied in limited Phase I and II trials in children in a variety of tumour types. These studies did not provide sufficient data to establish the efficacy and safety of Gemcitabin Hexal in children. Or, as directed by the registered physicians.

There is no known antidote for overdoses of Gemcitabin Hexal. Myelosuppression, paresthesias and severe rash were the principal toxicities seen when a single dose as high as 5700 mg/m2 was administered by IV infusion over 30 minutes every 2 weeks to several patients in a Phase 1 study. In the event of suspected overdose, the patient should be monitored with appropriate blood counts and should receive supportive therapy, as necessary.

Cytotoxic Chemotherapy

Store the vial in original carton at 20° to 25°C, away from light. Do not refrigerate as crystallisation may occur. Keep out of the reach of children.