Gemcitabine

263.2

263.20

1308068-626-2

B76N6SBZ8R

DTXSID3040487

C66876

Crystals from water, pH = 8.5

L01BC05|L - Antineoplastic and immunomodulating agents

29349990

108

-1.5

Solid

1.8±0.1 g/cm3

72.6 °C

482.7°C at 760 mmHg

236.8±31.5 °C

1.652

H2O: soluble

1.7X10-9 mm Hg at 25 deg C (est)

LD10 i.v. in rats: 200 mg/m2 (Abbruzzese)

365 +425.36°; D +71.51°

3.6None

Henry's Law constant = 1.7X10-17 atm-cu m/mol at 25 °C (est)

3.6|pKa1 = 5.27 (imine); pKa2 = 11.24 (alcohol) (est)

White to off-white solid. MW: 299.66. Soluble in water, slightly soluble in methanol, and practically insoluble in ethanol and polar solvents. /Hydrochloride/|Hydroxyl radical reaction rate constant = 4.0X10-13 cu cm/molec-sec at 25 °C (est)|Ozone reaction rate constant = 1.7X10-16 cu cm/molec-sec at 25 °C (est)

21-36/38-46-62-63

25-26-36/37-53

Xn,Xi

P201, P202, P260, P264, P270, P273, P280, P281, P301+P312, P302+P352, P305+P351+P338, P308+P313, P312, P314, P321, P322, P330, P332+P313, P337+P313, P362, P363, P391, P405, P501

H302

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ All contaminated disposables should be contained in sealable bags for transfer to larger waste containers. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ All bottles must be discarded as contaminated waste after decontamination of the biohazard cabinet. All protective apparel (gown, gloves, goggles, and respirator) should be discarded as contaminated waste. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The contaminated filters must be removed, bagged in thick plastic and prepared for disposal in a hazardous waste dump site or incinerator licensed by the Environmental Protection Agency (EPA). /Antineoplastic agents/|For more Disposal Methods (Complete) data for GEMCITABINE (8 total), please visit the HSDB record page.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl gemcitabine hydrochloride approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Gemcitabine hydrochloride/

|Danger|H302 (25%): Harmful if swallowed [Warning Acute toxicity, oral]|P201, P202, P260, P264, P270, P273, P280, P281, P301+P312, P302+P352, P305+P351+P338, P308+P313, P312, P314, P321, P322, P330, P332+P313, P337+P313, P362, P363, P391, P405, and P501|Aggregated GHS information provided by 4 companies from 4 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Protective apparel: Disposable closed-front gown or coveralls, disposable utility gloves over disposable latex gloves, NIOSH-approved air-purifying half-mask respirator equipped with a high efficiency filter, and eye protection should be worn. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Class 100 clean-air work stations, both horizontal and vertical airflow (with no containment characteristics), are inappropriate engineering controls for handling hazardous drugs because they provide no personnel protection and permit environmental contamination. Although there are no engineering controls designed specifically for the safe handling of hazardous chemicals as sterile products, Class II contained vertical-flow biological safety cabinets (biohazard cabinets) have been adopted for this use. Biohazard cabinetry is, however, designed for the handling of infectious agents, not hazardous chemicals. ... Based on design, ease of use, and cost considerations, Class II contained-vertical-flow biohazard cabinetry is currently recommended for use in preparing sterile doses of hazardous drugs. Class II cabinetry design and performance specifications are defined in NSF Standard 49. Biological safety cabinets selected for use with hazardous drugs should meet NSF Standard 49 specifications to ensure the maximum protection from these engineering controls. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Workers should wear powder free, disposable surgical latex gloves of good quality when preparing hazardous drugs. Selection criteria for gloves should include thickness (especially at the fingertips where stress is the greatest), fit, length, and tactile sensation. ... The practice of double gloving is supported by research that indicates that many glove materials vary in drug permeability even within lots; therefore, double gloving is recommended. ... In general, surgical latex gloves fit better, have appropriate elasticity for double gloving and maintaining the integrity of the glove-gown interface, and have sufficient tactile sensation (even during double gloving) for stringent aseptic procedures. ... Powdered gloves should be avoided. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Workers who are not protected by the containment environment of a biohazard cabinet should use respiratory protection when handling hazardous drugs. Respiratory protection should be an adjunct to and not a substitute for engineering controls. Surgical masks of all types provide no respiratory protection against powdered or liquid aerosols of hazardous drugs. In situations where workers may be exposed to potential eye contact with hazardous drugs, an appropriate plastic face shield or splash goggles should be worn. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ During compounding of hazardous drugs (eg, crushing, dissolving, and preparing an ointment), workers should wear low permeability gowns and double gloves. Compounding should take place in a protective area such as a disposable glove box. If compounding must be done in the open, an area away from drafts and traffic must be selected, and the worker should use appropriate respiratory protection. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Accidental contamination of the health-care environment, resulting in exposure of personnel, patients, visitors, and family members to hazardous substances, is prevented by maintaining the physical integrity and security of packages of hazardous drugs. 1. Access to all areas where hazardous drugs are stored is limited to specified authorized staff. 2. A method should be present for identifying to personnel those drugs that require special precautions (eg, cytotoxics). One way to accomplish this is to apply appropriate warning labels to all hazardous drug containers, shelves, and bins where the drug products are stored. ... 3. A method of identifying, for patients and family members, those drugs that require special precautions in the home should be in place. This may be accomplished in the health-care setting, by providing specific labeling for discharge medications, along with written instructions. 4. Methods for identifying shipping cartons of hazardous drugs should be required from manufacturers and distributors of these drugs. 5. Written procedures for handling damaged packages of hazardous drugs should be maintained. Personnel involved in shipping and receiving hazardous drugs should be trained in these procedures, including the proper use of protective garments and equipment. Damaged shipping cartons of hazardous drugs should be received and opened in an isolated area (eg, in a laboratory fume hood, if available, not in a vertical laminar airflow biological safety cabinet used for preparing sterile products). /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Facilities (eg, shelves, carts, counters, and trays) for storing hazardous drugs are designed to prevent breakage and to limit contamination in the event of leakage. Bins, shelves with barriers at the front, or other design features that reduce the chance of drug containers falling to the floor should be used. Hazardous drugs requiring refrigeration should be stored separately from nonhazardous drugs in individual bins designed to prevent breakage and to contain leakage. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Until the reproductive risks (or lack thereof) associated with handling hazardous drugs within a safety program have been substantiated, staff who are pregnant or breast-feeding should be allowed to avoid contact with these drugs. Policies should be in effect that provide these individuals with alternative tasks or responsibilities if they so desire. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The pharmacy should provide access to information on toxicity, treatment of acute exposure (if available), chemical inactivators, solubility and stability of hazardous drugs (including investigational agents) used in the workplace. /Antineoplastic agents/|For more Preventive Measures (Complete) data for GEMCITABINE (20 total), please visit the HSDB record page.

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Methods for transporting hazardous drugs to the health-care setting should be consistent with environmental protection and national or local regulations for transporting hazardous substances. When hazardous drugs are being transported to the home-care setting, appropriate containers (eg, lined cardboard boxes) and procedures should be used to prevent breakage and contain leakage. ... The drugs must be securely capped or sealed and properly packaged and protected during transport to reduce further the chance of breakage and spillage in a public area such as a corridor or elevator. /Antineoplastic agents/

Myelosuppression, paresthesias, and severe rash were the principal toxicities, LD50=500 mg/kg (orally in mice and rats)

Elevations in serum aminotransferase levels occur in 30% to 90% of patients receiving cyclic therapy with gemcitabine. The elevations are generally mild-to-moderate, asymptomatic and self-limited, frequently resolving without discontinuation or even interruption of therapy. ALT or AST elevations above 5 times the upper limit of the normal range occur in 1-4% of patients yet rarely lead to symptoms or clinically apparent liver injury. Serum bilirubin and alkaline phosphatase elevations are less common, but also typically transient and mild. Despite wide use, gemcitabine has only rarely been implicated in rare cases of acute liver injury with jaundice, and most published cases have been reported in patients with underlying chronic liver disease or extensive hepatic metastases. The clinical features of hepatotoxicity from gemcitabine have not been well described. Most cases were marked by a progressive cholestasis and hepatic failure developing after several cycles of therapy in patients with preexisting chronic liver disease (hepatitis C, alcoholic liver disease) or significant hepatic metastases or local invasion.

... /The authors/ present the first case of a nonlung cancer patient experiencing not only acne-like skin toxicity, but subsequently also severe interstitial lung disease during therapy with gemcitabine and erlotinib. Both therapeutic agents were suspected as a possible cause of this adverse event. An interaction between gemcitabine and erlotinib might have also contributed to the pathogenesis of this pulmonary toxicity. Treatment with high-dose steroids was, however, very effective in our patient and a complete recovery appeared within a few days. Thus, pulmonary side effects should be regarded carefully in pancreatic cancer patients receiving palliative therapy with gemcitabine and erlotinib.|/The authors/ investigated the possible pharmacokinetic interactions of gemcitabine and oxaliplatin in patients with advanced solid tumors. Ten patients with advanced stage solid tumors were treated with gemcitabine (1500 mg/sq m) as a 30-min intravenous infusion on days 1 and 8, followed by oxaliplatin (130 mg/sq m) as a 4-hr intravenous infusion, on day 8 every 21 days. Pharmacokinetic data for 24 hr after dosing were obtained for both day 1 (gemcitabine without oxaliplatin coadministration) and day 8 (gemcitabine with oxaliplatin) during the first cycle of treatment. Gemcitabine levels in plasma were quantified using a reverse-phase high-performance liquid chromatography assay with ultraviolet detection, and total and ultrafiltrated platinum levels by flameless atomic absorption spectrophotometry with deuterium correction. All pharmacokinetic parameters of gemcitabine seemed to be unchanged when coadministered with oxaliplatin (day 8) compared with pharmacokinetic data of gemcitabine given as a single agent (day 1). The mean (maximum) concentration of gemcitabine on days 1 and 8 was 13.57 (+/-7.42) and 10.23 (+/-5.21) mg/L, respectively (P=0.28), and the mean half-life was 0.32 and 0.44 hr, respectively (P=0.40). Similarly, the P-values for AUC0-24 and the observed clearance were 0.61 and 0.30, respectively. Plasma total and free platinum levels were in agreement with other published data. Gemcitabine disposition appeared to be unaffected by oxaliplatin coadministration because no significant changes in pharmacokinetics between day 1 (gemcitabine without oxaliplatin coadministration) and day 8 (gemcitabine with oxaliplatin) were observed.

... Gemcitabine is characterized by a narrow therapeutic index, and its liver elimination depends upon a key enzymatic step, driven by cytidine deaminase (CDA). CDA is prone to gene polymorphism, including the 208A>G mutation, which can result in marked enzymatic deficiency with subsequent impact on drug exposure levels and related toxicities. We have developed a simple and inexpensive method to determine phenotypically CDA status in cancer patients, as an attempt to detect those at risk upon gemcitabine intake. Conjointly to genotypic investigations, this method was used to phenotype, in a retrospective setting, a female patient displaying extremely severe, and eventually lethal, toxicities after administration of a standard gemcitabine/carboplatin protocol. Phenotypic investigation showed a marked CDA deficiency (-75%) in this patient when compared with a reference, nontoxic population. Genetic studies undertaken next to screen mutations, possibly at the origin of this deficiency, showed heterozygosity for the 79A>C single-point mutation, whereas surprisingly the canonical CDA 208A>G polymorphism was not found. Taken together, this case report demonstrates, for the first time, that CDA downregulation can lead to toxic-death in patients exposed to gemcitabine. ...

Plasma protein binding is negligible (<10%)

While data specific to gemcitabine were not located(SRC, 2007), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2). Studies have indicated that several polar pharmaceutically active compounds can leach through soil(1).

It is not known wether gemcitabine or its metabolites are distributed into breast milk.

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ ... exposure may be through inadvertent ingestion of the drug on foodstuffs (eg, workers' lunches), inhalation of drug dusts or droplets or direct skin contact. /Antineoplastic agents/

Gemcitabine is indicated for the treatment of advanced ovarian cancer that has relapsed at least 6 months after completion of platinum-based therapy; metastatic ovarian cancer; inoperable, locally advanced (Stage IIIA or IIIB), or metastatic (Stage IV) non-small cell lung cancer; and locally advanced (nonresectable Stage II or Stage III) or metastatic (Stage IV) adenocarcinoma of the pancreas.|FDA Label

Gemcitabine is a cytosine analogue and intravenously administered antineoplastic agent used in the therapy of several forms of advanced, pancreatic, lung, breast, ovarian and bladder cancer. Gemcitabine is associated with a high rate of transient serum enzyme elevations during therapy but is a very rare cause of acute, clinically apparent liver injury.

Antineoplastic Agents

Gemcitabine has known transformation products that include 2',2'-Difluorodeoxyuridine.

Antineoplastic|Gemcitabine in combination with paclitaxel is indicated for the first-line treatment of patients with metastatic breast cancer after the failure of prior anthracycline-containing adjuvant chemotherapy, unless anthracyclines are clinically contraindicated. /Included in US product label/|Gemcitabine is indicated as first-line therapy for locally advanced (nonresectable stage II or III) or metastatic (stage IV) adenocarcinoma of the pancreas. It is also indicated as second-line therapy for patients who have previously been treated with fluorouracil. Treatment with gemcitabine is primarily palliative. /Included in US product label/|Gemcitabine is indicated in combination with cisplatin as a first-line therapy for inoperable, locally advanced (Stage IIIA or IIIB) or metastatic (Stage IV) non-small cell lung carcinoma. /Included in US product label/|For more Therapeutic Uses (Complete) data for GEMCITABINE (9 total), please visit the HSDB record page.

A complete blood cell count (CBC), including differential and platelets, should be performed prior to each dose of gemcitabine. If myelosuppression is detected, therapy should be modified or temporarily withheld according to the degree of hematologic toxicity. For patients with absolute granulocyte counts of at least 1000/cu m and platelet counts of at least 100,000/cu m, no adjustment in dosage is necessary. For those with absolute granulocyte counts of 500-999/cu m or platelet counts of 50,000-99,000/cu m, 75% of the full dose should be given weekly. If the absolute granulocyte count is less than 500/cu m or the platelet count is less than 50,000/cu m, the weekly dose should be withheld until the counts exceed these levels.|The diagnosis of hemolytic-uremic syndrome should be considered and gemcitabine should be discontinued immediately in patients who develop anemia with evidence of microangiopathic hemolysis, elevation of serum bilirubin or LDH, reticulocytosis, and/or severe thrombocytopenia with or without evidence of renal failure (e.g., elevation of serum creatinine or BUN).|Gemcitabine should be discontinued immediately and appropriate supportive care (e.g., diuretics, corticosteroids) provided promptly in patients who develop severe adverse pulmonary effects.|The bone marrow depressant effects of gemcitabine may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding. Dental work, whenever possible, should be completed prior to the initiation of therapy or deferred until blood counts have returned to normal. Patients should be instructed in proper hygiene during treatment, including caution in use of regular toothbrushes, dental floss, and toothpicks.|FDA Pregnancy Risk Category: D /POSITIVE EVIDENCE OF RISK. Studies in humans, or investigational or post-marketing data, have demonstrated fetal risk. Nevertheless, potential benefits from the use of the drug may outweigh the potential risk. For example, the drug may be acceptable if needed in a life-threatening situation or serious disease for which safer drugs cannot be used or are ineffective./

Gemcitabine is an antineoplastic anti-metabolite. Anti-metabolites masquerade as purine or pyrimidine - which become the building blocks of DNA. They prevent these substances becoming incorporated in to DNA during the "S" phase (or DNA synthesis phase of the cell cycle), stopping normal development and division. Gemcitabine blocks an enzyme which converts the cytosine nucleotide into the deoxy derivative. In addition, DNA synthesis is further inhibited because Gemcitabine blocks the incorporation of the thymidine nucleotide into the DNA strand. It demonstrates dose-dependent synergistic activity with cisplatin in vitro. In vivo, gemcitabine showed activity in combination with cisplatin against the LX-1 and CALU-6 human lung xenografts, but minimal activity was seen with the NCI-H460 or NCI-H520 xenografts. Gemcitabine was synergistic with cisplatin in the Lewis lung murine xenograft. Sequential exposure to gemcitabine 4 hours before cisplatin produced the greatest interaction.

Agents used in the prophylaxis or therapy of VIRUS DISEASES. Some of the ways they may act include preventing viral replication by inhibiting viral DNA polymerase; binding to specific cell-surface receptors and inhibiting viral penetration or uncoating; inhibiting viral protein synthesis; or blocking late stages of virus assembly. (See all compounds classified as Antiviral Agents.)|Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. (See all compounds classified as Enzyme Inhibitors.)|Antimetabolites that are useful in cancer chemotherapy. (See all compounds classified as Antimetabolites, Antineoplastic.)|Agents that suppress immune function by one of several mechanisms of action. Classical cytotoxic immunosuppressants act by inhibiting DNA synthesis. Others may act through activation of T-CELLS or by inhibiting the activation of HELPER CELLS. While immunosuppression has been brought about in the past primarily to prevent rejection of transplanted organs, new applications involving mediation of the effects of INTERLEUKINS and other CYTOKINES are emerging. (See all compounds classified as Immunosuppressive Agents.)|Drugs used to potentiate the effectiveness of radiation therapy in destroying unwanted cells. (See all compounds classified as Radiation-Sensitizing Agents.)

The pharmacokinetics of gemcitabine are described by a 2-compartment model.|Within one (1) week, 92% to 98% of the dose was recovered, almost entirely in the urine. Gemcitabine (<10%) and the inactive uracil metabolite, 2´-deoxy-2´,2´-difluorouridine (dFdU), accounted for 99% of the excreted dose.|50 L/m^2 [infusions lasting <70 minutes]|92.2 L/hr/m2 [Men 29 yrs]|Gemcitabine pharmacokinetics are linear and are described by a 2-compartment model. Population pharmacokinetic analyses of combined single and multiple dose studies showed that the volume of distribution of gemcitabine was significantly influenced by duration of infusion and gender. Clearance was affected by age and gender. Differences in either clearance or volume of distribution based on patient characteristics or the duration of infusion result in changes in half-life and plasma concentrations.|Protein binding /of gemcitabine/ is very low, less than 10%.|It is not known wether gemcitabine or its metabolites are distributed into breast milk.|/Elimination is/ renal. 92 to 98% of a single dose of radiolabeled gemcitabine (1000 mg per square meter of body surface area, given over 30 minutes to five patients) was recovered within 1 week, primarily as the inactive uracil metabolite (approximately 89% of the excreted dose) and secondarily as unchanged gemcitabine (less than 10% of the excreted dose).|For more Absorption, Distribution and Excretion (Complete) data for GEMCITABINE (8 total), please visit the HSDB record page.

Transformed via nucleoside kinases to two active metabolites, gemcitabine diphosphate and gemcitabine triphosphate. Can also undergo deamination via cytidine deaminase to an inactive uracil metabolite (dFdU).|Gemcitabine undergoes intracellular metabolism, via nucleoside kinases, to produce two active metabolites (gemcitabine diphosphate and gemcitabine triphosphate) and also undergoes deamination to an active uracil metabolite.|... After intravenous injection, gemcitabine is rapidly converted to the inactive metabolite 2'-deoxy-2',2'-difluorouridine by cytidine deaminase. ...

Gemcitabine half-life for short infusions ranged from 42 to 94 minutes, and the value for long infusions varied from 245 to 638 minutes, depending on age and gender, reflecting a greatly increased volume of distribution with longer infusions.|The current study was performed in nonhuman primates to determine the plasma and CSF pharmacokinetics of gemcitabine and its inactive metabolite, difluorodeoxyuridine (dFdU) following iv administration. Gemcitabine, 200 mg/kg, was administered iv over 45 min to four nonhuman primates. Serial plasma and CSF samples were obtained prior to, during, and after completion of the infusion for determination of gemcitabine and dFdU concentrations. ... Plasma elimination was rapid with a mean t1/2 of 8 +/- 4 min (mean +/- SD) for gemcitabine and 83 +/- 8 min for dFdU. Gemcitabine total body clearance (ClTB) was 177 +/- 40 mL/min per kg and the Vdss was 5.5 +/- 1.0 L/kg. The maximum concentrations (Cmax) and areas under the time concentration curves (AUC) for gemcitabine and dFdU in plasma were 194 +/- 64 uM and 63.8 +/- 14.6 uM.hr, and 783 +/- 99 uM and 1725 +/- 186 uM.hr, respectively. The peak CSF concentrations of gemcitabine and dFdU were 2.5 +/- 1.4 uM and 32 +/- 41 uM, respectively. The mean CSF:plasma ratio was 6.7% for gemcitabine and 23.8% for dFdU. There is only modest penetration of gemcitabine into the CSF after iv administration.|In this study, the plasma pharmacokinetics (PKs) of gemcitabine and dFdU are further explored after gemcitabine doses of 10, 30, and 60 mg/kg administered by intravenous infusion with a loading dose /to dogs/. Gemcitabine displayed linear PKs, while the kinetics of 2',2'-difluorodeoxyuridine (dFdU) were not dose proportional. The overall clearance, volume of distribution at steady-state, and terminal elimination half-life (t(1/2)) for gemcitabine were 0.421 L/hr.kg, 0.822 L/kg, and 1.49 hr, respectively. Plasma concentrations of dFdU peaked at approximately 2 hr postdosing and had a t(1/2) of 14.9 hr.

Gemcitabine inhibits thymidylate synthetase, leading to inhibition of DNA synthesis and cell death. Gemcitabine is a prodrug so activity occurs as a result of intracellular conversion to two active metabolites, gemcitabine diphosphate and gemcitabine triphosphate by deoxycitidine kinase. Gemcitabine diphosphate also inhibits ribonucleotide reductase, the enzyme responsible for catalyzing synthesis of deoxynucleoside triphosphates required for DNA synthesis. Finally, Gemcitabine triphosphate (diflurorodeoxycytidine triphosphate) competes with endogenous deoxynucleoside triphosphates for incorporation into DNA.|Gemcitabine hydrochloride, a synthetic pyrimidine nucleoside, is an antineoplastic agent. The nucleoside analog consists of the pyrimidine base difluorocytidine, and the sugar moiety deoxyribose. Like most antimetabolite antineoplastic agents, gemcitabine is cell-cycle specific, acting principally in the S phase of the cell cycle; the drug also may cause cellular arrest at the G1-S border. The cytotoxic activity of gemcitabine (2'-deoxy-2',2'-difluorocytidine) depends on intracellular conversion to its 5'-diphosphate and -triphosphate metabolites; thus, deoxydifluorocytidine-5?-diphosphate (dFdCDP, gemcitabine diphosphate) and -triphosphate (dFdCTP, gemcitabine triphosphate) and not unchanged gemcitabine are the pharmacologically active forms of the drug. Gemcitabine is phosphorylated by deoxycytidine kinase to gemcitabine monophosphate, which subsequently is phosphorylated to the corresponding diphosphate and triphosphate nucleosides, presumably by deoxycytidylate kinase and nucleoside diphosphate kinase, respectively. The cytotoxic effect of gemcitabine is attributed to the combined actions of its diphosphate and triphosphate nucleosides, which lead to inhibition of DNA synthesis.|Gemcitabine diphosphate inhibits ribonucleotide reductase, which is responsible for catalyzing the formation of deoxynucleoside triphosphates needed in DNA synthesis. By inhibiting this reductase, gemcitabine diphosphate interferes with subsequent de novo nucleotide production. Gemcitabine triphosphate inhibits DNA synthesis by competing with the physiologic substrate, deoxycytidine triphosphate, for DNA polymerase and incorporation into DNA. The reduction in intracellular concentrations of deoxycytidine triphosphate induced by gemcitabine diphosphate actually enhances the incorporation of gemcitabine triphosphate into DNA, a mechanism referred to as ''self-potentiation.'' Following incorporation of gemcitabine triphosphate into the DNA chain, a single additional nucleotide, a normal base pair, is added and DNA synthesis is terminated, resulting in apoptosis (programmed cell death). DNA polymerase ? is unable to recognize the abnormal (gemcitabine) nucleotide and repair the DNA strand as a result of masking by the terminal normal base pair nucleotide (masked chain termination). This inability to recognize and excise the abnormal nucleotide results in a prolonged intracellular half-life of gemcitabine compared with other nucleoside analogs such as cytarabine and is thought to contribute to gemcitabine's expanded spectrum of antineoplastic activity relative to such agents. In CEM T lymphoblastoid cells, gemcitabine induces internucleosomal DNA fragmentation, which is characteristic of programmed cell death.

4-aminopyrimidin-2(1H)-one; 4-amino-1-(2-deoxy-2,2-difluoro-alpha-D-erythro-pentofuranosyl)pyrimidin-2(1h)-one

Emergency and supportive measures. Maintain an open airway and assist ventilation if necessary. Treat coma, seizures, hypotensin, and arrhythmias if they occur. Treat nausea and vomiting with metoclopramide and fluid loss caused by gastroenteritis with intravenous crystalloid fluids. /Antineoplastic agents/|Bone marrow depression should be treated with the assistance of an experienced hematologist or oncologist. /Antineoplastic agents/|Decontamination. Administer activated charcoal orally if conditions are appropriate. Gastric lavage is not necessary after small to moderate ingestions if activated charcoal can be given promptly. /Antineoplastic agents/|Enhanced elimination. Because of the rapid intracellular incorporation of most of these agents, dialysis and other extracorporeal removal procedures are generally not effective. /Antineoplastic agents/

/CASE REPORTS/ ... Three patients presented to two major teaching hospitals with significant pulmonary dysfunction while receiving gemcitabine. Case data were obtained from patient records. A review of the literature was done to seek reports of pulmonary toxicity with gemcitabine and cytosine arabinoside (ara-C). The common features of the respiratory illnesses of the three patients in this study were tachypnea, marked hypoxemia, and an interstitial infiltrate on chest radiograph consistent with pulmonary edema. There was no evidence of underlying heart disease in any patient. In addition, there was no evidence of infection, metabolic causes, or lymphangitic carcinomatosis to explain the clinical findings. Two patients died, and postmortem examination confirmed acute RDS (respiratory distress syndrome), whereas in the third patient a transbronchial biopsy showed interstitial pneumonitis. These findings were consistent with drug-induced pulmonary toxicity. Diuretics and corticosteroids were useful measures for treating the patients' symptoms, and one patient survived after gemcitabine was withdrawn. These three cases of acute RDS may be the result of a capillary leak phenomenon due to treatment with gemcitabine, as observed in patients given intermediate dose and high dose ara-C, a drug similar in structure and metabolism to gemcitabine.|/CASE REPORTS/ /Investigators/ report the case of a 75-year-old man with stage IV non-small-cell lung carcinoma treated with combination of gemcitabine 1000 mg/sq m and cisplatin 75 mg/sq m repeated every 28 days, who developed bilateral cutaneous bullous lesions of lower limbs following gemcitabine administration. Histopathologic examination did not show any toxidermy aspect and there was not any sign of immunoglobulin deposit in direct immunofluorescence test. Chemotherapy was stopped and lesions disappeared without any treatment. Even delayed with regard to gemcitabine administration, the causal relationship of gemcitabine treatment with skin reaction is possible according to the Naranjo probability scale.|/CASE REPORTS/ A 43-year-old woman with postpartum cardiomyopathy and ischemic heart disease was treated with gemcitabine for metastatic nonsmall cell lung cancer. Three days after her 5th treatment with gemcitabine, she developed chest pain and was diagnosed as having acute, non-q-wave myocardial infarction. She made an uneventful recovery. An objective causality assessment revealed that the adverse event was possible. Gemcitabine has been previously reported to be causative of acute myocardial infarction. Ischemic complications of chemotherapeutic agents are discussed.|/CASE REPORTS/ /Investigators/ hereby report a case of radiation recall dermatitis and myositis occurring on gemcitabine monotherapy, five months after completing chemoradiation for locally advanced pancreatic cancer. Radiation recall resolved spontaneously with withdrawal of gemcitabine. This ... case report ... describes gemcitabine-induced radiation recall in rectus abdominus muscles after gemcitabine-based radiation therapy.|For more Human Toxicity Excerpts (Complete) data for GEMCITABINE (13 total), please visit the HSDB record page.

2',2'-DFDC

Parenteral gemcitabine for injection, for IV infusion: 200 mg (of gemcitabine) Gemzar (with mannitol), Lilly. One g (of gemcitabine) Gemzar (with mannitol), Lilly.

Analyte: gemcitabine hydrochloride; matrix: chemical identification; procedure: infrared absorption spectrophotometry with comparison to standards /gemcitabine hydrochloride/|Analyte: gemcitabine hydrochloride; matrix: chemical purity; procedure: liquid chromatography with detection at 275 nm and comparison to standards /gemcitabine hydrochloride/|Analyte: gemcitabine hydrochloride; matrix: pharmaceutical preparation (solid for injection); procedure: infrared absorption spectrophotometry with comparison to standards (chemical identification) /gemcitabine hydrochloride/|Analyte: gemcitabine hydrochloride; matrix: pharmaceutical preparation (solid for injection); procedure: retention time of the major peak of the liquid chromatogram with comparison to standards (chemical identification) /gemcitabine hydrochloride/|For more Analytic Laboratory Methods (Complete) data for GEMCITABINE (7 total), please visit the HSDB record page.

Analyte: gemcitabine; matrix: blood (plasma); procedure: high-performance liquid chromatography with ultraviolet detection at 272 nm; limit of detection: 50 ng/mL|Analyte: gemcitabine; matrix: blood (plasma); procedure: high-performance liquid chromatography with ultraviolet detection at 269 nm

Pharmaceuticals -> Antineoplastic and immunomodulating agents -> Antineoplastic agents -> Antimetabolites -> Pyrimidine analogues -> Cytostatics