Gecita 200/Gecita

200 mg: A white coloured lyophilized cake filled in 10 mL clear moulded glass vial USP Type-1 with 20 mm bromobutyl slotted rubber stopper & sealed with 20 mm blue colour flip off seal.
Each vial contains: Gemcitabine Hydrochloride USP eq. to Gemcitabine 200 mg.
1 g: A white coloured lyophilized cake filled in 50 mL clear moulded glass vial USP Type-1 with 20 mm bromobutyl slotted rubber stopper & sealed with 20 mm blue colour flip off seal.
Each vial contains: Gemcitabine Hydrochloride USP eq. to Gemcitabine 1 mg.

Pharmacotherapeutic group: Antineoplastic agents, pyrimidine analogues.
Pharmacology: Pharmacodynamics: Cytotoxic activity in cell cultures: Gemcitabine shows significant cytotoxic effects against a variety of cultured murine and human tumour cells. Its action is phase-specific such that gemcitabine primarily kills cells that are undergoing DNA synthesis (S-phase) and, under certain circumstances, blocks the progression of cells at the junction of the G1/S phase boundary. In vitro, the cytotoxic effect of gemcitabine is dependent on both concentration and time.
Anti-tumoural activity in preclinical models: In animal tumour models, anti-tumoural activity of gemcitabine is schedule-dependent.
When gemcitabine is administered daily, high mortality among the animals but minimal anti-tumoural activity is observed. 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.
Mechanism of action: Cellular metabolism and mechanism 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 effect of gemcitabine is due to inhibition of DNA synthesis by two mechanisms of action by dFdCDP and dFdCTP. First, dFdCDP inhibits ribonucleotide reductase, which is uniquely responsible for catalysing the reactions that produce deoxynucleoside triphosphates (dCTP) for DNA synthesis. Inhibition of this enzyme by dFdCDP reduces the concentration of deoxynucleosides in general and, in particular, 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 reduced intracellular concentration of dCTP potentiates the incorporation of dFdCTP into DNA. DNA polymerase epsilon lacks the ability to eliminate gemcitabine and to 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 appears to induce the programmed cell 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 1000 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 of the 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 1000 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 refers to these cells. Intracellular concentrations increase in proportion to gemcitabine doses of 35-350 mg/m2/30-minutes, which give steady state concentrations of 0.4-5 μg/mL. At gemcitabine plasma concentrations above 5 μg/mL, dFdCTP levels do not increase, suggesting that the formation is saturable in these cells.
Half-life of terminal elimination: 0.7-12 hours.
dFdU kinetics: Peak plasma concentrations (3-15 minutes after end of 30-minute infusion, 1000 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 hr).
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 (range 1-4 V/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.

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.

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.
Gemcitabine 100 mg/mL concentrate for solution for infusion contains 440 mg ethanol anhydrous per mL concentrate. This should be taken into consideration in high-risk groups such as patients with liver disease or epilepsy.
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 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 with held until toxicity has resolved in the opinion of the physician.
Or as prescribed by the physician.

There is no known antidote for overdose of gemcitabine hydrochloride. 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.

Hypersensitivity to the active substance or to any of the excipients.
Breastfeeding.

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 leucopenia, thrombocytopenia 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.
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.
Capillary leak syndrome (CLS): Capillary leak syndrome has been reported in patients receiving gemcitabine as single agent or in combination with chemotherapeutic agents. 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. Gemcitabine 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.
Posterior reversible encephalopathy syndrome: Reports of posterior reversible encephalopathy syndrome (PRES) with potentially severe consequences have been reported in patients receiving gemcitabine as single agent or in combination with other chemotherapeutic agents. 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. Gemcitabine should be permanently discontinued and supportive measures implemented, including blood pressure control and anti-seizure therapy, if PRES develops during therapy.
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: Haemolytic uraemic syndrome: Clinical findings consistent with the haemolytic uraemic syndrome (HUS) were rarely reported in patients of microangiopathic haemolytic anaemia, such as rapidly falling haemoglobin with concomitant thrombocytopenia, 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.
Sodium: Gemcitabine 100 mg/mL Concentrate for solution for Infusion contains 199.6 mg (8.68 mmol) of sodium per maximum daily dose (2250 mg). This should be taken into consideration by patients on a controlled sodium diet.
Ethanol: Gemcitabine 100 mg/L concentrate for solution for infusion contains 440 mg ethanol anhydrous per mL concentrate. This may be harmful in patients suffering from alcoholism and should also be taken into consideration in high-risk groups such as patients with liver disease or epilepsy. Consideration should be given to possible effects on the central nervous system and other effects.
Hepatic insufficiency: Administration of gemcitabine in patients with concurrent liver metastases or a preexisting 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.

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 hydrochloride, 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.
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.

The most commonly reported adverse drug reactions associated with Gemcitabine 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.
The following table of undesirable effects and frequencies is based on data from clinical trials. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. (See table.)

Click on icon to see table/diagram/image

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 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 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 hydrochloride.
Others: Yellow fever and other live attenuated vaccines are not recommended due to the risk of systemic, possibly fatal, disease, particularly in immunosuppressed patients.
The amount of alcohol in this medicinal product may alter the effects of other medicines.

Direction for Reconstitution: For 200 mg vial: Reconstitute with 5 mL of 0.9% w/v Sodium Chloride Injection USP and shake gently to make a clear solution. Each mL of reconstituted solution contains 38 mg of Gemcitabine.
The reconstituted solution should be used immediately or within 24 hours if stored below 30°C.
For 1 g vial: Reconstitute with 25 mL of 0.9% w/v Sodium Chloride Injection USP and shake gently to make a clear solution. Each mL of reconstituted solution contains 38 mg of Gemcitabine.
The reconstituted solution should be used immediately or within 24 hours if stored below 30°C.
Do not refrigerate.
Single Dose Vial.

Store at temperatures not exceeding 30°C.

Cytotoxic Chemotherapy

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

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