Gemtero

Gemcitabine.

GEMTERO Lyophilized powder for injection 200 mg, each vial contains: Gemcitabine Hydrochloride equivalent to Gemcitabine 200 mg.
GEMTERO Lyophilized powder for injection 1 g, each vial contains: Gemcitabine Hydrochloride equivalent to Gemcitabine 1 g.

Pharmacology: Pharmacodynamics: Cellular metabolism and mechanism of action: Gemcitabine (dFdc) is metabolised intracellularly by nucleoside kinase 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. 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.

Non-small cell lung cancer: Gemcitabine in combination with Cisplatin is indicated as first line treatment of patients with locally advanced (inoperable stage IIIA and IIIB) or metastatic (stage IV) non-small cell lung cancer. Gemcitabine is indicated for the palliative treatment of adult patients with locally advanced or metastatic non-small cell lung cancer.
Pancreatic cancer: Gemcitabine is indicated as first-line treatment of patients with locally advanced (non-resectable Stage II or Stage III) or metastatic (Stage IV) adenocarcinoma of the pancreas. Gemcitabine is also indicated for patients previously treated with 5-FU.
Bladder cancer: Gemcitabine is indicated for treatment of advanced bladder cancer (muscle invasive Stage IV tumours with or without metastases) in combination with Cisplatin therapy.
Breast cancer: 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 as Anthracycline unless clinically contraindicated.
Ovarian cancer: Gemcitabine, alone or in combination, is indicated for the treatment of patients with recurrent epithelial ovarian carcinoma who have relapsed following platinum-based therapy.
Other therapeutic activity: Gemcitabine alone or in combination has shown activity in advanced breast and ovarian cancer.

Non-small cell lung cancer: Combination use: 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 minutes intravenous infusion on days 1, 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 minutes 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 after administration of Gemcitabine on day 1 of each 21-day or 28-day cycle.
Single agent use: Adults: The recommended doses is 1000 mg/m², given by 30 minutes intravenous infusion. This should be repeated once weekly for three weeks, followed by one week rest period. This four weeks cycle is then repeated. Dosage reduction is 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 minutes 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 is applied based upon the amount of toxicity experienced by the patient.
Bladder Cancer: Combination use: Adults: The recommended dose of Gemcitabine is 1000 mg/m², given by 30 minutes infusion. The dose should be given on days 1, 8 and 15 of each 28 days cycle in combination with Cisplatin. Cisplatin is given at a recommended dose of 70 mg/m² on day 1 following Gemcitabine on day 2 of each 28 days cycle. This four weeks 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. Myelosuppression is more common when Cisplatin was used in doses of 100 mg/m².
Breast cancer: Combination use: Adults: 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 30 minutes 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. Patients should have an absolute granulocyte count of at least 1500 (x10⁶/L) prior to initiation of Gemcitabine + Paclitaxel combination.
Ovarian cancer: Single agent use: Adults: The recommended dose of Gemcitabine is 800 - 1250 mg/m², given by a 30 minutes intravenous infusion. The dose should be given on days 1, 8 and 15 of each 28 cycles. This four weeks 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: Adults: Gemcitabine in combination with Carboplatin is recommended using Gemcitabine 1000 mg/m² on days 1 and 8 of each 21-day cycle as a 30 minutes intravenous infusion. After Gemcitabine, Carboplatin will be given on day 1 consistent with a target AUC of 4.0 mg/mL/minute. Dosage reduction with each cycle or within a cycle may be applied based upon the amount of toxicity. Patients receiving Gemcitabine should be monitored prior to each dose of platelet, leucocyte and granulocyte counts and, if necessary, the dose of Gemcitabine may be either reduced or withheld in the presence of haematological toxicity, according to the following scale: see table.


Click on icon to see table/diagram/image


For Cisplatin dosage adjustment in combination therapy, see the manufacturer's prescribing information.
Periodic checks of liver and kidney function, including transaminases and serum creatinine, should also be performed in patients receiving Gemcitabine.
Gemcitabine is well tolerated during the infusion, with only a few cases of injection site reaction reported.
Gemcitabine can be easily administered on an outpatient basis.
Elderly Patients: Gemcitabine has been well tolerated in patients over the age of 65. There is no evidence to suggest that dose adjustments are necessary in the elderly, although Gemcitabine clearance and half-life are affected by age.
Children: These studies did not provide sufficient data to establish efficacy and safety of Gemcitabine in children.
Hepatic and renal impairment: Gemcitabine should be used with caution in patient with hepatic insufficiency or with impaired renal function as there is insufficient information to allow clear dose recommendation for these patient population.

There is no antidote for overdosage of Gemcitabine. In the event of suspected overdose, the patient should be monitored with appropriate blood counts and should receive supportive therapy, as necessary.

Gemcitabine is contraindicated in those patients with a known hypersensitivity to the drug.

Prolongation of the infusion time and increased dosing frequency have been shown to increase toxicity.
Gemcitabine can suppress bone marrow function as manifested by leucopenia, thrombocytopenia and anemia. However, myelosuppression is short lived and usually does not result in dose reductions and rarely in discontinuation. Gemcitabine should be discontinued at the first signs of any evidence of microangiopathic haemolytic anemia such as rapidly falling hemoglobin with concomitant thrombocytopenia, elevation of serum bilirubin, serum creatinine, blood urea nitrogen, or LDH, which may indicate development of hemolytic uremic syndrome. Renal failure may not be reversible, even with discontinuation of therapy, and dialysis may be required.
Serious spontaneous reports of haemolytic uremic syndrome (HUS), capillary leak syndrome (CLS), adult respiratory distress syndrome (ARDS), and 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. These events can be related to vascular endothelial injury possibly induced by Gemcitabine. Gemcitabine should be discontinued and supportive measures implemented if any of these develop during therapy.
In addition to ARDS, other severe pulmonary effects such as interstitial pneumonitis and pulmonary edema have been reported in patients receiving Gemcitabine as single agent or in combination with other chemotherapeutic agents. Gemcitabine should be discontinued and supportive measures provided if these effects develop during therapy.

General: Patients receiving therapy with Gemcitabine must be monitored closely. Laboratory facilities should be available to monitor patient status. Treatment for a patient compromised by drug toxicity may be required.
Laboratory test: Therapy should be started cautiously in patients with compromised bone marrow function. As with other oncolytics, the possibility of cumulative bone marrow suppression when using combination or sequential chemotherapy should be considered. 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 marrow depression is detected. Peripheral blood counts may continue to fall after the drug is stopped. Laboratory evaluation of renal and hepatic function should be performed periodically. 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.
Interaction with 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. Gemcitabine has radiosensitizing activity. Significant toxicity in the form of severe, and potentially life-threatening mucositis, especially esophagitis and pneumonitis was observed, particularly in patients receiving large volumes of radiotherapy (median treatment volumes 4,795 cm³). The optimum regimen for safe administration of Gemcitabine with therapeutic doses of radiation has not yet been determined.
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. esophagitis, colitis and pneumonitis) in association with both concurrent and non-concurrent use of Gemcitabine.
Effects on ability to drive and use machines: Gemcitabine has been reported to cause mild to moderate somnolence. Patients should be cautioned against driving or operating machinery until it is established that they do not become somnolent.
Use in pregnancy and lactation: The safety of this medicinal product for use in human pregnancy has not been established. The use of Gemcitabine should be avoided in pregnant or nursing women because of the potential hazard to the fetus or infant.

The safety of this medicinal product for use in human pregnancy has not been established. The use of Gemcitabine should be avoided in pregnant or nursing women because of the potential hazard to the fetus or infant.

Haematological: Because Gemcitabine is a bone marrow suppressant, anemia, leucopenia and thrombocytopenia can occur as a result of administration of Gemcitabine. Myelosuppression is usually mild to moderate and is more pronounced for the granulocyte count. Thrombocytaemia is also very rarely reported. Febrile neutropenia is also commonly reported.
Gastro-intestinal: Nausea and nausea accompanied by vomiting are each reported in about one-third of patients, respectively. This adverse event requires therapy, is rarely dose-limiting and is easily manageable with standard antiemetics.
Renal: Mild proteinuria and hematuria 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 of renal failure of uncertain aetiology have been reported, including in very rare instances, cases of haemolytic uraemic syndrome (HUS) in patients receiving Gemcitabine. Hence, Gemcitabine should be used with caution in patients with impaired renal function.
Allergic: Anaphylaxis has been reported rarely.
Respiratory: Bronchospasm after Gemcitabine infusion has been reported and bronchospasm is usually mild and transient, but parenteral therapy may be required. Gemcitabine should not be administered to patients with a known hypersensitivity to this drug.
Dyspnoea occurring within hours following Gemcitabine injection is reported and is usually mild, short lived, rarely dose-limiting, and usually abates without any specific therapy. The mechanism of this event is unknown and the relationship to Gemcitabine is not clear. Pulmonary effects, sometimes severe (such as pulmonary oedema, interstitial pneumonitis, or adult respiratory distress syndrome - ARDS) have been reported rarely in association with Gemcitabine therapy.
Hepatobiliary system: Abnormalities of liver transaminase enzymes (AST and ALT) and alkaline phosphatase occur in about two-thirds of patients, but they are usually mild, non-progressive and rarely necessitate stopping treatment. However, Gemcitabine should be used with caution in patients with impaired liver function. Elevation in gamma-glutamyl transferase (GGT) and bilirubin levels have been reported rarely.
Injury, poisoning and procedural complications: Radiation toxicity and radiation recall reactions have been reported.
Cardiovascular: A few cases of hypotension were reported. Cases of myocardial infarction, congestive heart failure and arrhythmia have been reported, but there is no clear evidence that Gemcitabine causes cardiac toxicity.
Vascular system: Peripheral vasculitis and gangrene, and capillary leak syndrome have been reported very rarely.
Skin and subcutaneous tissue: A rash is seen in patients and is associated with pruritus in patients. The rash is usually mild, not dose-limiting and responds to local therapy. Desquamation, vesiculation and ulceration have been reported rarely. Severe skin reactions, including desquamation and bullous skin eruptions have been reported very rarely.
Nervous system: Posterior reversible encephalopathy syndrome has been reported very rarely.
Others: An entity resembling is reported. This is usually mild, short-lived and rarely dose-limiting. Fever, headache, back pain, chills, myalgia, asthenia and anorexia are the most commonly reported symptoms. Cough, rhinitis, malaise, sweating and insomnia are also commonly reported. Fever and asthenia are also reported frequently as isolated symptoms. The mechanism of this toxicity is unknown. Reports received indicate that Paracetamol may produce symptomatic relief.
Oedema/peripheral oedema is reported. Some cases of facial edema have also been reported. Oedema/peripheral oedema is usually mild to moderate, rarely dose-limiting, is sometimes reported as painful and is usually reversible after stopping Gemcitabine treatment. The mechanism of this toxicity is unknown. It is not associated with any evidence of cardiac, hepatic or renal failure.
The following adverse effect are also commonly reported: Alopecia (usually minimal hair loss), somnolence, diarrhea, oral toxicity (mainly soreness and erythema) and constipation.

Instructions for use/handling: Reconstitution: Gemcitabine has only been shown to be compatible with 0.9% Sodium Chloride Injection. Accordingly, only this diluent should be used for reconstitution. Compatibility with other drugs has not been studied, therefore, it is not recommended to mix GEMTERO with other drugs when reconstituted. Due to solubility considerations, the maximum concentration for Gemcitabine upon reconstitution is 40 mg/mL. Reconstitution at concentrations greater than 40 mg/mL may result in incomplete dissolution, and should be avoided.
To reconstitute, add at least 5 mL of 0.9% Sodium Chloride Injection to the 200 mg vial (GEMTERO 200 mg) or at least 25 mL of 0.9% Sodium Chloride Injection to the 1 g vial (GEMTERO 1 g). Shake to dissolve. The appropriate amount of drug may be administered as prepared or further diluted with 0.9% Sodium Chloride Injection. Reconstituted solution should be used immediately or may be stored for 24 hours if prepared in an appropriately controlled aseptic environment. Parenteral drugs should be inspected visually for particulate matter and discoloration, prior to administration, whenever solution and container permit.
Guidelines for the safe handling of antineoplastic agents: Cytotoxic preparations should not be handled by pregnant staff. Trained personnel should reconstitute the drug. This should be performed in a designated area. The work surface should be covered with disposable plastic-backed absorbent paper.
Adequate protective gloves, masks clothing should be worn. Precautions should be taken to avoid the drug accidentally coming into contact with the eyes. If accidental contamination occurs, the eye should be washed with water thoroughly and immediately. Use luer-lock fitting on all syringes and sets. Large bore needles are recommended to minimize pressure and the possible formation of aerosols. The latter may also be reduced by the use of a venting needle.
Adequate care and precaution should be taken in the disposal of items used to reconstitute GEMTERO. Any unused dry product or contaminated materials should be placed in a high risk waste bag. Sharp objects (needles, syringe, 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 incineration. Any excess drug solution should be flushed directly into a drain with copious amounts of water.

Store below 30°C.
Shelf life after reconstitution: For reconstitution: GEMTERO 200 mg: Add 5 mL of 0.9% Sodium Chloride Injection to the 200 mg vial. Shake to dissolve.
GEMTERO 1 g: Add 25 mL of 0.9% Sodium Chloride Injection to the 1 g vial. Shake to dissolve.
When prepared as directed, Gemcitabine solution remains stable during 24 hours at temperature below 30°C. Solution of reconstituted Gemcitabine should not be refrigerated.

Cytotoxic Chemotherapy

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

G