Abingem

Gemcitabine hydrochloride.

A white to off white lyophilized mass.
Each vial contains: Gemcitabine (as Hydrochloride) USP 1 g.

Pharmacotherapeutic group: Pyrimidine analogues. ATC code: L01BC05.
Pharmacology: Pharmacodynamics: Cytotoxic Activity in Cell Culture Models: Gemcitabine exhibits significant cytotoxicity activity against a variety of cultured murine and human tumour cells. It exhibits cell phase specificity, primarily killing cells undergoing DNA synthesis (S-phase) and under certain conditions blocking the progression of cells through the G1/S-phase boundary. In vitro the cytotoxic action of gemcitabine is both concentration and time dependent.
Antitumour Activity in Preclinical Models: In animal tumour models, the antitumour activity of gemcitabine is schedule dependent. When gemcitabine is administered daily, high animal mortality but minimal antitumoural activity is seen. If, however, gemcitabine is given every third or fourth day, it can be administered in non-lethal doses with substantial antitumoural activity against a broad spectrum of mouse tumours.
Cellular Metabolism and Mechanisms of Action: Gemcitabine (dFdC), which is a pyrimidine antimetabolite, is metabolised intracellularly by nucleoside kinase to the active diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides. The cytotoxic action of gemcitabine is due to inhibition of DNA synthesis by two actions of dFdCDP and dFdCTP. First, dFdCDP inhibits ribonucleotide reductase, which is uniquely responsible for catalyzing the reactions that generate the deoxynucleoside triphosphates (dCTP) for DNA synthesis. Inhibition of this enzyme by dFdCDP causes reduction in the concentrations of deoxynucleosides in general, and especially in that of dCTP. Second, dFdCTP competes with dCTP for incorporation into DNA (self-potentiation).
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. 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.
Pharmacokinetics: The pharmacokinetics of gemcitabine have been examined in 353 patients in seven studies. The 121 women and 232 men ranged in age from 29 to 79 years. Of these patients, approximately 45% had non-small cell lung cancer and 35% were diagnosed with pancreatic cancer. The following pharmacokinetic parameters were obtained for doses ranging from 500 to 2,592 mg/m² that were infused from 0.4 to 1.2 hours.
Peak plasma concentrations (obtained within 5 minutes of the end of the infusion) were 3.2 to 45.5 μg/mL. Plasma concentrations of the parent compound following a dose of 1,000 mg/m²/30-minutes are greater than 5 μg/mL for approximately 30-minutes after the end of the infusion, and greater than 0.4 μg/mL for an additional hour.
Distribution: The volume of distribution in central compartment was 12.4 L/m² for women and 17.5 L/m² for men (inter-individual variability was 91.9%). The volume of distribution of the peripheral compartment was 47.4 L/m². The volume of the peripheral compartment was not sensitive to gender.
The plasma protein binding was considered to be negligible.
Half-life: This ranged from 42 to 94 minutes depending on age and gender. For the recommended dosing schedule, gemcitabine elimination should be virtually complete within 5 to 11 hours of the start of the infusion. Gemcitabine does not accumulate when administered once weekly.
Metabolism: Gemcitabine is rapidly metabolised by cytidine deaminase in the liver, kidney, blood, and other tissues.
Intracellular metabolism of gemcitabine produces the gemcitabine mono-, di-, and triphosphates (dFdCMP, dFdCDP, and dFdCTP), of which dFdCDP and dFdCTP are considered active. These intracellular metabolites have not been detected in plasma or urine.
The primary metabolite, 2-deoxy-2',2'-difluorouridine (dFdU), is not active and is found in plasma and urine.
Excretion: Systemic clearance ranged from 29.2 L/hr/m² to 92.2 L/hr/m² depending on gender and age (inter-individual variability was 52.2%). Clearance for women is approximately 25% lower than the values for men. Although rapid, clearance for both men and women appears to decrease with age. For the recommended gemcitabine dose of 1,000 mg/m² given as a 30 minute infusion, lower clearance values for women and men should not necessitate a decrease in the gemcitabine dose.
Urinary excretion: Less than 10% is excreted as unchanged drug.
Renal clearance was 2 to 7 L/hr/m².
During the week following administration, 92 to 98% of the dose of gemcitabine administered is recovered, 99% in the urine, mainly in the form of dFdU and 1% of the dose is excreted in faeces.
dFdCTP Kinetics: This metabolite can be found in peripheral blood mononuclear cells and the information as follows refer to these cells.
Intracellular concentrations increase in proportion to gemcitabine doses of 35-350 mg/m²/30 min, which give steady-state concentrations of 0.4-4.5 μg/mL. At gemcitabine plasma concentrations above 5 μg/mL, dFdCTP level do not increase, suggesting that the formation is saturable in these cells.
Half-life terminal elimination: 0.7-12 hours.
dFdU Kinetics: Peak plasma concentrations (3-15 minutes after end of 30 minute infusion, 1,000 mg/m²): 28-52 μg/mL.
Trough concentration following once weekly dosing: 0.07-1.12 μg/mL, with no apparent accumulation.
Triphasic plasma concentration versus time curve, mean half-life of terminal phase: 65 hours (range 33-84 hours).
Formation of dFdU from parent compound: 91%-98%.
Mean volume of distribution of central compartment: 18 L/m² (range 11-22 L/m²).
Mean steady-state volume of distribution (Vss): 150 L/m² (range 96-228 L/m²).
Tissue distribution: Extensive.
Mean apparent clearance: 2.5 L/hr/m² (range1-4 L/hr/m²).
Urinary excretion: All.
Gemcitabine and Paclitaxel Combination Therapy: Combination therapy did not alter the pharmacokinetics of either gemcitabine or paclitaxel.
Gemcitabine and Carboplatin Combination Therapy: When given in combination with carboplatin the pharmacokinetics of gemcitabine were not altered.
Renal impairment: Mild to moderate renal insufficiency (GFR from 30 mL/min to 80 mL/min) has no consistent, significant effect on gemcitabine pharmacokinetics.

Bladder Cancer: Locally advanced or metastatic bladder cancer, in combination with cisplatin.
Pancreatic Cancer: Locally advanced or metastatic adenocarcinoma of the pancreas.
Non-Small Cell Lung Cancer: First-line treatment of patients with locally advanced or metastatic non-small cell lung cancer, in combination with cisplatin. Gemcitabine monotherapy can be considered in elderly patients or those with performance status 2.
Ovarian cancer: 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.
Breast Cancer: Unresectable, locally recurrent 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.

For intravenous infusion, following reconstitution. Upon reconstitution a colourless or slightly yellow solution is produced.
Gemcitabine should only be prescribed by a physician qualified in the use of anti-cancer chemotherapy.
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 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 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.
Pancreatic Cancer: 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 of rest period. Subsequent cycles should consist of gemcitabine infusions once weekly for 3 consecutive weeks out of every four weeks. Dosage reduction with each cycle or within a cycle may be applied, based upon the amount of toxicity experienced by the patient.
Non-Small Cell Lung Cancer (Monotherapy): 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 with each cycle or within a cycle may be applied, based upon the amount of toxicity experienced by the patient.
Non-Small Cell Lung Cancer (Combination Therapy): Adults: The recommended dose of gemcitabine is 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.
Cisplatin has been used at doses between 75-100 mg/m² once every 3 weeks.
Ovarian cancer (combination therapy): The recommended dose of gemcitabine, when used in combination with carboplatin, is 1000 mg/m², given by 30 minute intravenous infusion, on days 1 and 8 of each 21 day cycle. After gemcitabine, carboplatin will be given on day 1, consistent with a target Area Under the Curve (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.
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 the gemcitabine + paclitaxel combination.
Monitoring for toxicity and dose modification due to toxicity: Dose adjustment 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 cycle may be applied, based upon the amount of toxicity experienced by the patient. In general, for severe (Grade 3 or 4) non-haematological toxicity, except nausea/vomiting, therapy with gemcitabine should be withheld or decreased depending on the judgement of the treating physician. Doses should be withheld until toxicity has been resolved.
For cisplatin, carboplatin, and paclitaxel dosage adjustment in combination therapy, please refer to the corresponding Summary of Product Characteristics.
Dosage Adjustment in the Presence of Haematological Toxicity: Initiation of a cycle: For all indications, 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 a platelet count of 100,000 (x10⁶/L) prior to administration 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 Adjustment 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 <0.5 x 10⁹/L for more than 5 days; Absolute granulocyte count <0.1 x 10⁹/L for more than 3 days; Febrile neutropaenia; Platelets <25 x 10⁹/L, Cycle delay of more than one week due to toxicity.
Methods 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 Hepatic or Renal Impairment: Gemcitabine should be used with caution in patients with hepatic or renal impairment as there is insufficient information from clinical studies to allow for clear dose recommendations for these patient populations (see Precautions and Pharmacology: Pharmacokinetics under Actions).
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 (see Pharmacology: Pharmacokinetics under Actions).
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.

Myelosuppression, paresthesias, and severe rash were the principal toxicities seen when a single dose as high as 5700 mg/m² can be administered by intravenous infusion over 30 minutes every 2 weeks. In the event of suspected overdose, the patient should be monitored with appropriate blood counts and provide supportive therapy, as necessary. There is no known antidote for overdose of gemcitabine.

Hypersensitivity to gemcitabine or to any of the excipients.
Breast-feeding.

Prolongation of infusion time and increased dosing frequency have been shown to increase in 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 Impairment: Administration of gemcitabine to patients with concurrent liver metastases or a pre-existing medical history of hepatitis, alcoholism or cirrhosis of the liver may result in exacerbation of the underlying liver impairment.
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 given to discontinuing gemcitabine therapy. Early use of supportive care measures may help ameliorate the condition.
Renal: Clinical findings consistent with the haemolytic uraemic syndrome (HUS) were rarely reported in patients receiving gemcitabine. HUS is a life-threatening disease. Treatment should be discontinued at the first signs of any evidence of micro-angiopathic haemolytic anaemia, such as rapidly falling haemoglobin levels with concurrent thrombocytopenia, elevation of serum bilirubin, serum creatinine, blood urea nitrogen or lactate dehydrogenase (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 (0.15 mmol) sodium per vial. This should be taken into consideration by patients on a sodium-controlled diet.
Gemcitabine 1 g contains 17.5 mg (0.75 mmol) sodium per vial. This should be taken into consideration by patients on sodium-controlled diet.
Gemcitabine 1 g contains 35 mg (1.5 mmol) sodium per vial. This should be taken into consideration by patients on sodium-controlled diet.

Pregnancy: There are no adequate data from the use of gemcitabine in pregnant patients. 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.
Lactation: It is now known whether gemcitabine is excreted in human milk and adverse events 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 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.

The most commonly reported adverse reactions associated with gemcitabine treatment include: nausea, with or without vomiting, and raised liver transaminases (AST/ALT) 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 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.
Clinical trial data: Frequencies are defined as: 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). (See Table 4.)

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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 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.
Grade 3 and 4 Adverse Events, Paclitaxel Versus Gemcitabine plus Paclitaxel: (See Table 5.)

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Combination use in bladder cancer: Grade 3 and 4 Adverse Events, MVAC versus gemcitabine plus cisplatin: (See Table 6.)

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Combination use in ovarian cancer: Grade 3 and 4 Adverse Events, Carboplatin versus gemcitabine plus carboplatin: (See Table 7.)

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Sensory neuropathy was also more frequent in the combination arm that with single agent carboplatin.

When Gemcitabine (1250 mg/m² on Days 1 and 8) and cisplatin (75 mg/m² on Day 1) were administered in patients with Non-small cell lung cancer (NSCLC), the clearance of gemcitabine on Day 1 was 128 L/hr/m² and on Day 8 was 107 L/hr/m². Data from patients with NSCLC demonstrate that Gemcitabine and carboplatin given in combination does not alter the pharmacokinetics of gemcitabine or carboplatin compared to administration of either single agent; however due to wide confidence intervals and small sample size, interpatient variability may be observed.
Data from metastatic breast cancer patients shows that gemcitabine has little or no effect on the pharmacokinetics (clearance and half-life) of paclitaxel and paclitaxel has little or no effect on the pharmacokinetics of gemcitabine.

Instructions and Special Precautions for Handling and Disposal: Reconstitution: For single use only.
This medicinal product has only been shown to be compatible with sodium chloride 9 mg/mL (0.9% w/v) solution for injection. Accordingly, only this diluent should be used for reconstitution. Compatibility with other active substances has not been studied. Therefore, it is not recommended to mix this medicinal product with other active substances when reconstituted.
Reconstitution at concentrations greater than 38 mg/mL may result in incomplete dissolution, and should be avoided.
To reconstitute, slowly add the appropriate volume of sodium chloride 9 mg/mL (0.9% w/v) solution for injection (as stated in the table as follows) and shake to dissolve. (See Table 8.)

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The appropriate amount of medicinal product may be further diluted with sodium chloride 9 mg/mL (0.9% w/v) solution for injection.
Parenteral medicinal products should be inspected visually for particulate matter and discolouration, prior to administration, whenever solution and container permit.
Any unused solution should be discarded as described as follows.
Guidelines for the Safe Handling of Cytotoxic Medicinal Products: Local guidelines on safe preparation and handling of cytotoxic medicinal products must be adhered to. Cytotoxic preparations should not be handled by pregnant staff. The preparation of injectable solutions of cytotoxic agents must be carried out by trained specialist personnel with knowledge of the medicines used. This should be performed in a designated area. The work surface should be covered with disposable plastic-backed absorbent paper.
Suitable eye protection, disposable gloves, face mask and disposable apron should be worn. Precautions should be taken to avoid the medicinal product accidentally coming into contact with the eyes. If accidental contamination occurs, the eye should be washed with water thoroughly and immediately.
Syringes and infusion sets should be assembled carefully to avoid leakage (use of Luer lock fittings is recommended). Large bore needles are recommended to minimise pressure and the possible formation of aerosoles. The latter may also be reduced by the use of a venting needle.
Actual spillage or leakage should be mopped up wearing protective gloves. Excreta and vomit must be handled with care.
Disposal: Adequate care and precaution should be taken in the disposal of items used to reconstitute this medicinal product. Any unused dry product or contaminated materials should be placed in a high-risk waste bag. Sharp objects (needles, syringes, vials, etc) should be placed in a suitable rigid container. Personnel concerned with the collection and disposal of this waste should be aware of the hazard involved. Waste material should be destroyed by unused incineration. Any product or waste material should be disposed of in accordance with local requirements.

Store at temperature not exceeding 25°C. Protect from light. Do not refrigerate after reconstitution.
For Gemcitabine (as hydrochloride) 1 g Lyophilized Powder for Injection: Reconstitute 25 mL of Sodium Chloride Injection (0.9% w/v) and shake gently to make a clear solution containing 38 mg/mL to 40 mg/mL of Gemcitabine. Solution with precipitate to be discarded. Discard unused portion.

Cytotoxic Chemotherapy

L01BC05 - gemcitabine ; Belongs to the class of antimetabolites, pyrimidine analogues. Used in the treatment of cancer.

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