Gemtero

Gemtero

gemcitabine

Manufacturer:

Hetero Labs

Distributor:

Camber
Full Prescribing Info
Contents
Gemcitabine.
Description
Each vial contains: Gemcitabine hydrochloride equivalent to Gemcitabine 200 mg or Gemcitabine hydrochloride equivalent to Gemcitabine 1 g
Action
Pharmacology: Pharmacokinetics: After intravenous doses gemcitabine is rapidly cleared from the blood and metabolized by cytidine deaminase in the liver, kidney, blood, and other tissues. Clearance is about 25% lower in women than in men. Almost all of the dose is excreted in urine as 2'-deoxy-2',2'-difluorouridine (dFdU), only about 1% being found in the faeces. Intracellular metabolism produces mono-, di-, and triphosphate metabolites, the latter two active. The half-life of gemcitabine ranges from 42 to 94 minutes depending on age and gender. The intracellular half-life of the triphosphate is stated to range from 0.7 to 12 hours.
Indications/Uses
Gemcitabine is indicated for the treatment of locally advanced or metastatic bladder cancer in combination with cisplatin.
Gemcitabine is indicated for 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 performance status 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 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.
Dosage/Direction for Use
Gemcitabine should only be prescribed by a physician qualified in the use of anti-cancer chemotherapy.
Recommended posology: Bladder cancer: 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 grade 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 grade of toxicity experienced by the patient.
Non small Cell lung cancer: Monotherapy: The recommended dose of gemcitabine is 1000 mg/m2, given by 30-minute intravenous infusion. This should be repeated once weekly for 3 weeks, followed by a 1-week rest period. This 4-week cycle is then repeated. Dosage reduction with each cycle or within a cycle may be applied based upon the grade of toxicity experienced by the patient.
Combination use: The recommended dose for gemcitabine is 1250 mg/m2 body surface area given as a 30-minute intravenous infusion on Day 1 and 8 of the treatment cycle (21 days). Dosage reduction with each cycle or within a cycle may be applied 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: 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 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 + paclitaxel combination.
Ovarian cancer: Combination use: 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 will be given on Day 1 consistent with a target Area under curve (AUC) of 4.0 mg/mL·min. Dosage reduction with each cycle or within a cycle may be applied based upon the grade of toxicity experienced by the patient. Monitoring for toxicity and dose modification due to toxicity.
Dose modification due to non haematological toxicity: Periodic physical examination and checks of renal and hepatic function should be made to detect non-haematological toxicity. Dosage reduction with each cycle or within a cycle may be applied based upon the grade of toxicity experienced by the patient. In general, for severe (Grade 3 and 4) nonhaematological toxicity, except nausea/vomiting, therapy with gemcitabine should be withheld or decreased depending on the judgment of the treating physician. Doses should be withheld until toxicity has resolved in the opinion of the physician.
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 be monitored before each dose for platelet and granulocyte counts.
Patients should have an absolute granulocyte count of at least 1,500 (x106/L) and platelet account of 100,000 (x 106/L) prior to the initiation of a cycle.
Within a cycle: Dose modifications of gemcitabine within a cycle should be performed according to the following tables: See Tables 1, 2 and 3.

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Dose modifications due to haematological toxicity in subsequent cycles, for all indications: The gemcitabine dose should be reduced to 75% of the original cycle initiation dose, in the case of the following haematological toxicities: 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 more than 1 week due to toxicity.
Method of administration: Gemcitabine is tolerated well during infusion and may be administered ambulant. If extravasation occurs, generally the infusion must be stopped immediately and started again in another blood vessel. The patient should be monitored carefully after the administration.
Special populations: Patients with renal or hepatic impairment: Gemcitabine should be used with caution in patients with hepatic or renal insufficiency as there is insufficient information from clinical studies to allow for clear dose recommendations for these patient populations.
Elderly population (> 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.
Paediatric population (< 18 years): Gemcitabine is not recommended for use in children under 18 years of age due to insufficient data on safety and efficacy.
Overdosage
There is no known antidote for overdose of gemcitabine. Doses as high as 5700 mg/m2 have been administered by intravenous infusion over 30-minutes every 2 weeks with clinically acceptable toxicity. In the event of suspected overdose, the patient should be monitored with appropriate blood counts and receive supportive therapy, as necessary.
Contraindications
Hypersensitivity to the active substance or to any of the excipients. Breast-feeding.
Special Precautions
Prolongation of the infusion time and increased dosing frequency have been shown to increase toxicity.
Haematological toxicity: Gemcitabine can suppress bone marrow function as manifested by leucopaenia, thrombocytopaenia and anaemia.
Patients receiving gemcitabine should be monitored prior to each dose for platelet, leucocyte and granulocyte counts. Suspension or modification of therapy should be considered when drug-induced bone marrow depression is detected. 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 gemcitabine administration has been stopped. 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.
Hepatic insufficiency: Administration of gemcitabine 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 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.
Concomitant radiotherapy: Concomitant radiotherapy (given together or ≤7 days apart): Toxicity has been reported.
Live vaccinations: Yellow fever vaccine and other live attenuated vaccines are not recommended in patients treated with gemcitabine.
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.
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 gemcitabine therapy. Early use of supportive care measure may help ameliorate the condition.
Renal: Clinical findings consistent with the haemolytic uraemic syndrome (HUS) were rarely reported in patients receiving gemcitabine. 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.
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 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 gemcitabine.
Sodium: Gemcitabine 200 mg contains 3.5 mg (<1 mmol) sodium per vial. This should be taken into consideration by patients on a controlled sodium diet.
Gemcitabine 1000 mg contains 17.5 mg (<1 mmol) sodium per vial. This should be taken into consideration by patients on a controlled sodium diet.
Effects on Ability to Drive and Use Machines: No studies on the effects on the ability to drive and use machines have been performed. However, gemcitabine has been reported to 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.
Use In Pregnancy & Lactation
Use in Pregnancy: There are no adequate data from the use of gemcitabine in pregnant women. Studies in animals have shown reproductive toxicity. Based on results from animal studies and the mechanism of action of gemcitabine, this substance should not be used during pregnancy unless clearly necessary.
Women should be advised not to become pregnant during treatment with gemcitabine and to warn their attending physician immediately, should this occur after all.
Use in Lactation: 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 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 gemcitabine.
Adverse Reactions
The most commonly reported adverse drug reactions associated with Gemtero 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. Dose-limiting adverse reactions are reductions in thrombocyte, leucocyte and granulocyte counts.
Postmarketing experience (spontaneous reports) frequency not known (can't be estimated from the available data): Nervous system disorders: Cerebrovascular accident.
Cardiac disorders: Arrhythmias, 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.
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 Urinary disorders: Renal Failure, Haemolytic uraemic syndrome.
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. (See Table 4.)

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Combination use in bladder cancer: See Table 5.

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Combination use in ovarian cancer: See Table 6.

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Sensory neuropathy was also more frequent in the combination arm than with single agent Carboplatin.
Drug Interactions
No specific interaction studies have been performed.
Radiotherapy: Concurrent (given together or ≤ 7 days apart) - 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/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 4,795 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, where thoracic radiation doses of 66 Gy were applied concomitantly with an administration 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 in all tumour types.
Non-concurrent (given >7 days apart) - 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 suggest 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.
Others: Yellow fever and other live attenuated vaccines are not recommended due to the risk of systemic, possibly fatal, disease, particularly in immunosuppressed patients.
Caution For Usage
Direction for Reconstitution: Gemcitabine for injection 200 mg: Add 5 mL of 0.9% sodium chloride injection (without preservatives) to make a solution. Shake to dissolve. Administer solution within 24 hours. Discard unused portion.
Gemcitabine for injection 1 g: Add 25 mL of 0.9% sodium chloride injection (without preservatives) to make a solution. Shake to dissolve. Administer solution within 24 hours. Discard unused portion.
Storage
Store at temperatures not exceeding 30°C.
ATC Classification
L01BC05 - gemcitabine ; Belongs to the class of antimetabolites, pyrimidine analogues. Used in the treatment of cancer.
Presentation/Packing
Powd for soln for IV inj (vial) 200 mg x 12's. 1 g x 10's.
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