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Drug Details

Gemcitabine 200mg Powder for Solution for Infusion

• Drug Class Description
  Cytotoxics.
• Generic Name
  Gemcitabine
• Presentation
  Powder for solution for infusion (powder for infusion) White to off-white powder.
• Description
  Each vial contains 200 mg gemcitabine (as hydrochloride) Contains approximately 0.15 mmol (3.5 mg) sodium per 200 mg vial One ml of the reconstituted solution for infusion contains 38 mg gemcitabine (as hydrochloride).
• Indications
  

  Bladder Cancer: Locally advanced or metastatic bladder cancer in combination with cisplatin.

  Breast Cancer: Locally advanced or metastatic breast cancer in combination with paclitaxel in patients experiencing a relapse after adjuvant/neoadjuvant chemotherapy. The preceding chemotherapy should have included an anthracycline unless clinically contraindicated.

  Non-Small Cell Lung Cancer: Locally advanced or metastatic non-small cell lung cancer in combination with other cytostatic medicinal products. Palliative treatment of adult patients with locally advanced or metastatic non-small cell lung cancer.

  Pancreatic Cancer: Locally advanced or metastatic adenocarcinoma of the pancreas in patients who are in good general condition with adequate bone marrow reserves.

• Adult Dosage
  

  For intravenous infusion, following reconstitution.

  Upon reconstitution a colourless or slightly yellow solution is produced.

  Bladder cancer (combination therapy):

  Adults: The recommended dose for gemcitabine is 1000 mg/m², given as a 30 minute infusion. The dose should be given on day 1, 8, and 15 of each 28 day cycle in combination with cisplatin. Cisplatin is given at a dose of 70 mg/m² on day 1 following gemcitabine 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.

  Breast cancer (combination therapy):

  Adults: It is recommended that gemcitabine is used together with paclitaxel according to the following procedure:

  Paclitaxel (175 mg/m²) is intravenously infused over 3 hours on day 1 followed by gemcitabine (1250 mg/m²) intravenously infused for 30 minutes on days 1 and 8 of each 21 day treatment cycle. Dosage reduction with each cycle or within a cycle may be applied based upon the amount of toxicity experienced by the patient. The absolute granulocyte count should be at least 1.5 x 10⁹/l before treatment with gemcitabine + paclitaxel combination.

  Non-small cell lung cancer (combination therapy):

  Adults: Gemcitabine, in combination with cisplatin, has been investigated using two dosing regimens. One regimen used a three week schedule and the other 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.

  Cisplatin has been used at doses between 75-100 mg/m² once every 3 or 4 weeks.

  Non-small cell lung cancer (single agent use):

  Adults: 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 is applied based upon the amount of toxicity experienced by the patient.

  Cancer of the pancreas:

  Adults: 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 one week rest period. Subsequent cycles should consist of gemcitabine infusions once weekly for 3 consecutive weeks, followed by a one week rest period. Dosage reduction with each cycle or within a cycle may be applied based upon the amount of toxicity experienced by the patient.

  Dosage adjustment in the presence of haematological toxicity:

  Patients must be monitored before each dose for platelet, leucocyte, and granulocyte counts. The dose of gemcitabine must be either reduced or withheld in the presence of haematological toxicity according to the dose modifications below.

  Non-small cell lung cancer, bladder cancer and pancreatic cancer:

  Table 1 provides recommendations on the dose modification of gemcitabine when used as a single agent or in combination with cisplatin. Dosage adjustments based upon the following scale should occur at day 8 and/or day 15 within the 21 or 28 day cycle for non-small cell lung cancer and bladder cancer, and for any dose within the 7 or 3 week cycle for pancreatic cancer.

  Table 1

  Absolute Granulocyte Count (x 109/l)		Platelet Count (x 109/l)	% of Total Dose
  >1	and	>100	100
  0.5-1	or	50-100	75
  <0.5	or	<50	Withhold*

  *Treatment may be reinstated on day 1 of the next cycle.

  For cisplatin dosage adjustment in combination therapy, see the manufacturers' prescribing information.

  Breast cancer:

  Table 2 provides recommendations on dose modification of gemcitabine when used in combination with paclitaxel. Dosage adjustments based upon the following scale should occur at day 8 within the 21 day cycle for breast cancer.

  Table 2

  Absolute Neutrophil Count (x 109/l)		Platelet Count (x 109/l)	% of Total Dose
  ≥1.2	and	>75	100
  1-<1.2	or	50-75	75
  0.7-<1	and	≥ 50	50
  <0.7	or	<50	Withhold*

  *Treatment may be reinstated on day 1 of the next cycle.

  Dose adjustment of gemcitabine (in combination with paclitaxel) for subsequent cycles is based upon haematological toxicity. Patients who experienced sustained Grade 4 febrile neutropenia, required gemcitabine omission on days 8, or had a prolonged delay of the start of cycle (2 weeks) should receive 75% of the starting dose of the previous cycle. For day 8 dosing, gemcitabine will be administered at the same dose as day 1.

  For paclitaxel dosage adjustment in combination therapy, see the manufacturers' prescribing information.

  Hepatic and renal impairment:

  No studies have been done in patients with significant hepatic or renal impairment.

• Child Dosage
  

  Gemcitabine has not been studied in children. Use in children is not recommended.

• Elderly Dosage
  

  Gemcitabine has been well tolerated in patients over the age of 65. Although gemcitabine clearance and half-life is affected by age, there are no specific recommendations on dose adjustment for the elderly.

• Contra Indications
  

  Hypersensitivity to gemcitabine or to any of the excipients

  Breast-feeding during treatment with gemcitabine

  In combination with yellow fever vaccine

• Special Precautions
  

  Warnings:

  Prolongation of the infusion time and reduction of the recommended interval between doses increase toxicity.

  In rare cases kidney failure, including haemolytic uremic syndrome, have been reported. Treatment should be discontinued if signs of micro-angiopathic haemolytic anaemia, such as rapidly falling haemoglobin levels with concurrent thrombocytopenia, increase of serum bilirubin, serum creatinine, blood urea nitrogen or lactate dehydrogenase. The kidney failure can be irreversible, even if the treatment of gemcitabine have been discontinued, and may necessitate dialysis.

  Pulmonary effects, sometimes severe (such as pulmonary oedema, interstitial pneumonitis, or adult respiratory distress syndrome), have been reported rarely in association with gemcitabine therapy, see section 4.8. The aetiology of these effects is unknown. If severe pulmonary effects develop, gemcitabine must be discontinued. Early use of supportive care measures may help ameliorate the condition. The risk of adverse pulmonary reaction appears to be higher in patients with lung cancer and lung metastases than with other tumour types, which should be taken into consideration when treating such patients.

  Administration of gemcitabine to patients with liver metastases or a pre-existing medical history of hepatitis, alcoholism or cirrhosis of the liver may result in exacerbation of the underlying liver insufficiency.

  Interaction between gemcitabine and radiotherapy.

  If extravasation occurs, the infusion must be stopped immediately and started again in another blood vessel. The patient should be monitored carefully after the administration.

  Precautions:

  Treatment with gemcitabine should be started by, or in consultation with, a physician with considerable experience in the use of cytotoxic medicinal products.

  Patients receiving therapy with gemcitabine must be monitored closely. Laboratory facilities should be available to monitor patient status. Treatment for a patient compromised by toxicity may be required.

  In patients with impaired bone-marrow function, the treatment should be started with caution. As with other cytotoxic treatments, the risk of cumulative bone-marrow suppression must be considered when gemcitabine treatment is given together with other chemotherapy.

  Before each dose, thrombocyte, leucocyte and granulocyte counts must be checked. Peripheral blood levels may continue to deteriorate after gemcitabine treatment has been stopped.

  Gemcitabine must be used with caution in patients with renal impairment and hepatic impairment as there is insufficient information from clinical studies to allow clear dose recommendations for this group of patients.

  Periodic checks of liver and kidney functions, including transaminases and serum creatinine, should also be performed in patients receiving gemcitabine.

  Women of child-bearing potential should take steps to avoid pregnancy.

  Men being treated with gemcitabine are advised to use effective contraception.

• Interactions
  

  Radiotherapy:

  Concurrent (given together or 7 days apart): Based on the result of preclinical studies and clinical trials, gemcitabine has radiosensitising activity. In a single trial, where gemcitabine at a dose of 1000 mg/m² was administered concurrently for up to 6 consecutive weeks with therapeutic thoracic radiation to patients with non-small cell lung cancer, significant toxicity in the form of severe and potentially life-threatening mucositis, especially oesophagitis and pneumonitis, was observed, particularly in patients receiving large volumes of radiotherapy (median treatment volumes 4795 cm³). Studies done subsequently have suggested that it is feasible to administer gemcitabine at lower doses with concurrent radiotherapy with predictable toxicity, such as a Phase II study in non-small cell lung cancer. Thoracic radiation doses of 66 Gy were administered with gemcitabine (600 mg/m², four times) and cisplatin (80 mg/m², twice) during 6 weeks. The optimum regimen for safe administration of gemcitabine with therapeutic doses of radiation has not yet been determined.

  Sequential (given >7 days apart): Available information does not indicate any enhanced toxicity with administration of gemcitabine in patients who receive prior radiation, other than radiation recall. Data suggest that gemcitabine can be started after the acute effects of radiation have resolved or at least one week after radiation. Available information does not indicate any enhanced toxicity from radiation therapy following gemcitabine exposure.

  Oral anticoagulants (e.g. Warfarin):

  Increase frequency of INR (International Normalised Ratio) monitoring due to the potential for increased anticoagulant effects.

  Yellow fever vaccine:

  Contraindicated due to the potential risk of fatal systemic vaccinal disease.

  Live attenuated vaccines (except yellow fever):

  Concomitant use not recommended due to the risk of systemic, possible fatal, disease, particularly in immunosuppressed patients. Use of an inactivated vaccine is recommended where on exists (e.g. poliomyelitis).

  Phenytoin:

  Concomitant use is not recommended. Risk of exacerbation of convulsions due to decreased phenytoin gastrointestinal absorption. Risk of toxicity enhancement, or reduced efficacy of gemcitabine due to increased hepatic metabolism by phenytoin.

  Ciclosporin, tacrolimus:

  Excessive immunosuppression with risk of lymphoproliferation.

• Adverse Drug Reactions
  

  The most commonly reported adverse reactions associated with gemcitabine treatment include: nausea, with or without vomiting, and raised liver transaminases (aspartate aminotransferase/alanine aminotransferase) and alkaline phosphatase, reported in approximately 60% of patients; proteinuria and haematuria reported in approximately 50% of patients; dyspnoea reported in 10-40% of patients (highest incidence in lung cancer patients); allergic skin rashes occurring in approximately 25% of patients, and 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. Dose-limiting adverse reactions are reductions in platelet, leucocyte, and granulocyte counts.

  The following table of undesirable effects and frequencies is based on clinical trial and post-marketing spontaneous reports.

  Frequencies: Very common (1/10); common (1/100 to <1/10); uncommon (1/1,000 to <1/100); rare (1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data)

  Blood and lymphatic system disorders	Very common: Leucopenia, thrombocytopenia, neutropenia (frequency of grade 3 is 19.3% and of grade 4 is 6%), anaemia Bone marrow suppression is usually mild to moderate and mostly affects the granulocyte count Common: Febrile neutropeniaVery rare: Thrombocythaemia
  Immune system disorders	Very Rare: Anaphylactoid reaction
  Metabolism and nutrition disorders	Common: Anorexia
  Nervous system disorders	Common: Headache, somnolence, insomnia
  Cardiac disorders	Rare: Myocardial infarct, cardiac insufficiency, arrhythmia (predominantly supraventricular in nature)
  Vascular disorders	Rare: HypotensionVery rare: Clinical signs of peripheral vasculitis, gangrene
  Respiratory, thoracic and mediastinal disorders	Very common: Dyspnoea (usually mild and passes rapidly without treatment) Common: Cough, rhinitis Uncommon: Pulmonary oedema, bronchospasm, interstitial pneumonitis together with pulmonary infiltrates Rare: Adult respiratory distress syndrome
  Gastrointestinal disorders	Very common: Nausea, vomiting Common: Diarrhoea, constipation, stomatitis, ulceration of the mouth
  Hepatobiliary disorders	Very common: Elevation of liver transaminases (aspartate aminotransferase and alanine aminotransferase) and alkaline phosphatase Common: Increased bilirubinRare: Increased gamma glutamyl transferaseVery rare: Serious hepatotoxicity, including liver failure and death
  Skin and subcutaneous tissue disorders	Very common: Allergic skin rash frequently associated with pruritus (the rash is usually mild, not dose-limiting and responsive to local therapy), alopecia (usually mild with minimal hair loss) Common: Sweating, itchingRare: Scaling, vesicle formation, ulcerationVery rare: Severe skin reactions including ecdysis and bullous skin eruptions
  Musculoskeletal and connective tissue disorders	Common: Myalgia, back pain
  Renal and urinary disorders	Very common: Mild proteinurea, haematuria (rarely clinically significant, and not usually associated with any change in serum creatinine or blood urea nitrogen) Rare: Haemolytic uraemic syndrome, renal failure – may lead to death or require dialysis
  General disorders and administration site conditions	Very common: Oedema/peripheral oedema (the reaction is not associated with signs of cardiac, hepatic or renal insufficiency and is usually reversible after stopping treatment), influenza-like symptoms (the most common symptoms are fever, headache, back pain, shivering, muscle pain, asthenia, malaise and anorexia. Cough, rhinitis, sweating and sleeping difficulties have also been reported) Common: Fever, asthenia, facial oedemaRare: Injection site reactions (mainly mild in nature)
  Injury, poisoning and procedural complications	Very common: Radiation toxicity

  Gemcitabine plus paclitaxel:

  	Number (%) of Patients
  	Paclitaxel Arm(n= 259)		Gemcitabine plus Paclitaxel Arm(n= 262)
  	Grade 3	Grade 4	Grade 3	Grade 4
  Blood and Lymphatic
  Haemoglobin	5(1.9)	1 (0.4)	15 (5.7)	3 (1.1)
  Platelets	0	0	14 (5.3)	1 (0.4)
  Neutrophils/granulocytes	11 (4.2)	17 (6.6)*	82 (31.3)	45 (17.2)*
  Febrile neutropenia	3 (1.2)	0	12 (4.6)	1 (0.4)
  General Disorders and Administration Site Conditions
  Fatigue	3 (1.2)	1 (0.4)	15 (5.7)	2 (0.8)
  Gastro-intestinal Disorders
  Diarrhoea	5 (1.9)	0	8(3.1)	0
  * Grade 4 neutropenia lasting for more than 7 days occurred in 12.6% of patients in the combination arm and 5.0% of patients in the paclitaxel arm.

  The increase in these adverse reactions is not associated with an increased incidence of infections of 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.

  Gemcitabine plus cisplatin:

  An increase of the following grade 3 and 4 effects (gemcitabine + cisplatin versus MVAC (methotrexate, vinblastine, doxorubicin and cisplatin)) have been observed.

  Haematological toxicity:

  haemoglobin (G3: 24% and 16% respectively; G4: 4% and 2% respectively);

  thrombocytes (G3: 29% and 8% respectively; G4: 29% and 13% respectively).

  Non-haematological toxicity:

  Nausea and vomiting (G3: 22% and 19% respectively; G4: 0% and 2% respectively);

  diarrhoea (G3: 3% and 8% respectively; G4: 0% and 1% respectively);

  infection (G3: 2% and 10% respectively; G4: 1% and 5% respectively);

  stomatitis (G3: 1% and 18% respectively; G4: 0% and 4% respectively).

  Gemcitabine plus carboplatin:

  An increase of the following grade3 and 4 effects (gemcitabine + carboplatin versus carboplatin alone) have been observed.

  Haematological toxicity:

  haemoglobin (G3: 22.3% and 5.7% respectively; G4: 5.1% and 2.3% respectively);

  neutrophils (G3: 41.7% and 10.9% respectively; G4: 28.6% and 1.1% respectively);

  thrombocytes (G3: 30.3% and 10.3% respectively; G4: 4.6% and 1.1% respectively).

  Non-haematological toxicity:

  bleeding (G3: 1.8% and 0% respectively; G4: 0% and 0% respectively);

  neutropenia with fever (G3: 1.1% and 0% respectively; G4: 0% and 0% respectively);

  infection without neutropenia (G3: 0.6% and 0% respectively; G4: 0% and 0% respectively).