Brand name: Gemzar
Drug class: Antineoplastic Agents
VA class: AN300
Chemical name: 2′-Deoxy-2′,2′-difluoro-cytidine monohydrochloride
Molecular formula: C₉H₁₁F₂N₃O₄•ClH
CAS number: 122111-03-9

Medically reviewed by Drugs.com on Jul 1, 2024. Written by ASHP.

Introduction

Antimetabolite antineoplastic agent; a synthetic pyrimidine nucleoside.

Uses for Gemcitabine

Breast Cancer

Used in combination with paclitaxel as first-line therapy for metastatic breast cancer in patients who did not respond to previous anthracycline-containing chemotherapy or in whom such chemotherapy was contraindicated.

Non-small Cell Lung Cancer

Used for initial treatment in patients with inoperable, locally advanced (stage IIIA or IIIB) or metastatic (stage IV) non-small cell lung cancer in combination with cisplatin.

Used as monotherapy^{† [off-label]} for advanced non-small cell lung cancer in patients with relapsed or refractory advanced non-small cell lung cancer who previously were treated with platinum-containing chemotherapy regimens or in those who have not received prior chemotherapy.

Use of chemotherapy generally is advised only in patients with good performance status (ECOG performance status of 0 or 1, and 2 in selected patients) and evaluable lesions so that treatment can be discontinued if the disease does not respond. Individualize decision to use chemotherapy according to several factors, including patient preference, toxicity, survival benefit, quality of life, and cost of treatment.

Pancreatic Cancer

Used as first-line therapy for the palliative treatment of locally advanced (nonresectable stage II or III) or metastatic (stage IV) adenocarcinoma of the pancreas.

Also used as second-line therapy in patients previously treated with fluorouracil.

Bladder Cancer

Used alone or in combination therapy (i.e., cisplatin) for the treatment of advanced or metastatic bladder cancer^{† [off-label]}.

Objective responses to gemcitabine have been observed in patients with metastatic bladder cancer that did not respond to previous treatment with cisplatin-based regimens, including some patients with hepatic metastases.

Ovarian Cancer

Currently being investigated for use in the treatment of advanced epithelial ovarian cancer^{† [off-label]}.

Biliary Tract Cancer

Use in combination with cisplatin is recommended (accepted) for the treatment of unresectable locally advanced or metastatic biliary tract cancer^{† [off-label]} (intrahepatic or extrahepatic cholangiocarcinoma, gallbladder cancer, or ampullary cancer), including unresectable recurrent disease following surgical resection, in patients with good performance status (ECOG performance status of 0 or 1).

Gemcitabine Dosage and Administration

General

• Consult specialized references for procedures for proper handling and disposal of antineoplastics.

• Perform CBC, including differential and platelets, prior to each dose of gemcitabine. Modify or temporarily withhold dosage if myelosuppression is detected, according to the degree of hematologic toxicity. When used in combination with other antineoplastic agents, dosage modification of the concomitant agent also may be required for hematologic and/or nonhematologic toxicity.

Administration

IV Administration

Administer by IV infusion.

The drug is for IV use only.

For solution and drug compatibility information, see Compatibility under Stability.

Reconstitution

Reconstitute vials containing 200 mg or 1 g of gemcitabine by adding 5 or 25 mL, respectively, of 0.9% sodium chloride injection without preservatives to provide a solution containing 38 mg/mL (accounts for the displacement volume of lyophilized powder). Shake to dissolve.

Total volume upon reconstitution for vials labeled as containing 200 mg or 1 g is about 5.26 or 26.3 mL, respectively.

Smaller volumes should not be used for reconstitution; concentrations >38 mg/mL may exceed the solubility of the drug and result in incomplete dissolution.

Discard any unused portion after preparation of the appropriate dose.

Dilution

Reconstituted solutions can be infused IV without further dilution or as solutions that have been further diluted in 0.9% sodium chloride injection to concentrations as low as 0.1 mg/mL.

Rate of Administration

Infuse over a period of 30 minutes.

Prolonged IV infusion (>60 minutes) is associated with a prolonged half-life and increased toxicity, including clinically important myelosuppression. (See Elimination under Pharmacokinetics.) Infusion time should not exceed 60 minutes.

Dosage

Available as gemcitabine hydrochloride; dosage expressed in terms of gemcitabine.

Individualize dosage based on body surface area and patient tolerance and response.

Adults

Breast Cancer

IV

1.25 g/m² given on days 1 and 8 of a 21-day cycle; administer in combination with paclitaxel 175 mg/m², given on day 1, as a 3-hour infusion before administration of gemcitabine.

Patients should have an absolute granulocyte count of ≥1500/mm³ and platelet count of ≥100,000/mm³ prior to each cycle. Adjust dosage according to granulocyte and platelet counts obtained on day 8 of therapy (see Table 1).

If the patient experiences grade 3 or 4 nonhematologic toxicity (except alopecia, nausea/vomiting), therapy should be interrupted or dosage reduced by 50%, according to clinician’s judgment.

Non-small Cell Lung Cancer

Combination Therapy with Cisplatin

Optimum dosage regimen has not been established.

IV

1 g/m² administered on days 1, 8, and 15 of each 28-day cycle (4-week schedule) or 1.25 g/m² administered on days 1 and 8 of each 21-day cycle (3-week schedule). Administer cisplatin 100 mg/m² on day 1 following completion of the gemcitabine infusion.

If the patient experiences grade 3 or 4 nonhematologic toxicity (except alopecia, nausea/vomiting), therapy should be interrupted or dosage reduced by 50%, according to clinician’s judgment.

See Table 2 for gemcitabine dosage modification for hematologic toxicity.

Monotherapy

IV

1 or 1.25 g/m² once weekly for 3 weeks followed by 1 week of rest.

Pancreatic Cancer

Initial Dosing Cycle

IV

1 g/m² once weekly; repeat at weekly intervals as tolerated for up to 7 weeks, followed by a week of rest from treatment. If necessary, reduce or withhold dosage according to the degree of hematologic toxicity. (See Table 3 for dosage modification for hematologic toxicity.)

Subsequent Dosing Cycles

IV

1 g/m² once weekly for 3 consecutive weeks, followed by a week of rest from treatment.

Dosage may be increased to 1.25 g/m² weekly for 3 consecutive weeks, followed by a week of rest, in patients who successfully complete the initial 7-week or subsequent 3-week cycle of therapy at the full weekly dosage, provided nadirs of the absolute granulocyte and platelet counts are >1500 and 100,000/mm³, respectively, and WHO nonhematologic toxicity > grade 1 is not present. Dosage can be further increased to 1.5 g/m² weekly given in 3-week cycles if previous 3-week course is tolerated (i.e., hematologic parameters are met and no evidence of WHO nonhematologic toxicity >1).

If necessary, reduce or withhold dosage according to the degree of hematologic toxicity. (See Table 3.)

In clinical trials, patients received an average of 3 cycles of therapy.

Biliary Tract Cancer† [off-label]

IV

Gemcitabine 1 g/m² (as 30-minute infusion) has been given on days 1 and 8 of each 21-day cycle; administered in combination with cisplatin (25 mg/m² as 1-hour infusion on days 1 and 8 prior to gemcitabine). Treatment continued for 24 weeks (8 cycles) in the absence of disease progression or unacceptable toxicity.

Prescribing Limits

Do not administer more frequently than once weekly, since risk of toxicity is increased with such dosing. Infusion time should not exceed 60 minutes. (See Rate of Administration under Dosage and Administration.)

Special Populations

Hepatic Impairment

No specific recommendations for dosage adjustment; use with caution.

Renal Impairment

No specific recommendations for dosage adjustment; use with caution.

Geriatric Patients

Decreased clearance. No dosage adjustments in patients >65 years of age except those related to hematologic or nonhematologic toxicity (see Dosage under Dosage and Administration).

Female Patients

Decreased clearance. No dosage adjustments except those related to hematologic or nonhematologic toxicity (see Dosage under Dosage and Administration).

Cautions for Gemcitabine

Contraindications

• Known hypersensitivity to gemcitabine or any ingredient in the formulation.

Warnings/Precautions

Warnings

IV Administration

IV infusion over >60 minutes and administration more frequent than once weekly may be associated with increased toxicity (e.g., myelosuppression). (See Rate of Administration under Dosage and Administration.)

Hematologic Effects

Myelosuppression, including leukopenia, anemia, and thrombocytopenia, (usually dose-limiting) may require blood transfusions. Perform a CBC, including differential and platelets, prior to each dose; modify dosage accordingly.

Pulmonary Effects

Severe adverse pulmonary effects, sometimes fatal (e.g., pulmonary edema, interstitial pneumonitis, pulmonary fibrosis, ARDS), have been reported. Onset of pulmonary symptoms has occurred up to 2 weeks following administration of the last dose; rarely, respiratory failure and death have occurred despite discontinuance of therapy.

Dyspnea, occasionally accompanied by bronchospasm, has been reported. Possible dose-limiting pulmonary toxicity (e.g., esophagitis, pulmonary fibrosis, and pneumonitis) in patients receiving concurrent thoracic radiation therapy for non-small cell lung cancer.

Discontinue therapy immediately and institute appropriate supportive care (e.g., diuretics, corticosteroids) promptly in patients who develop severe adverse pulmonary effects.

Renal Effects

Risk of hemolytic-uremic syndrome and/or renal failure; rarely fatal or requires dialysis despite discontinuance of therapy. Discontinue therapy immediately and consider a diagnosis of hemolytic-uremic syndrome 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 S_cr or BUN).

Hepatic Effects

Severe hepatotoxicity, including hepatic failure and death, has been reported rarely.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; embryotoxic and fetotoxic in animals. If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard.

Sensitivity Reactions

Anaphylactoid reactions reported rarely.

General Precautions

Adequate Patient Evaluation and Monitoring

Administer only under close supervision of qualified clinician experienced in cancer chemotherapy. Adverse effects generally are reversible and do not require discontinuance of therapy; however, dosage adjustments may be required.

Assess renal and hepatic function prior to and periodically during therapy.

Specific Populations

Pregnancy

Category D. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether gemcitabine is distributed into human milk. Discontinue nursing because of potential risk to nursing infants.

Pediatric Use

Safety and efficacy not established in children <18 years of age.

Geriatric Use

Decreased clearance and increased half life. Possible increased incidence of severe (grade 3/4) thrombocytopenia.

Hepatic Impairment

Use with caution; assess hepatic function prior to and periodically during therapy.

Renal Impairment

Use with caution; assess renal function prior to and periodically during therapy.

Women

Decreased clearance. Women tolerate the drug more poorly than men, are less likely to progress to subsequent cycles, and are more likely to experience hematologic toxicity (i.e., neutropenia, thrombocytopenia).

Common Adverse Effects

Myelosuppression, transient elevations of serum AST and ALT, proteinuria, hematuria, nausea, vomiting, pain, constipation, fever, fatigue, rash, dyspnea, diarrhea, edema, flu-like symptoms, infection, alopecia, stomatitis, somnolence, paresthesias, and injection site reactions.

Gemcitabine Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations attained up to 30 minutes after discontinuance of the infusion.

Distribution

Extent

Volume of distribution increases with length of infusion. Not extensively distributed into tissues following IV infusion over <70 minutes (volume of distribution 50 L/m²). Following long infusion times, volume of distribution is 370 L/m², indicating slow equilibration into tissues.

Plasma Protein Binding

Negligible.

Special Populations

Volume of distribution is affected by gender.

Elimination

Metabolism

Converted intracellularly to active metabolites (gemcitabine diphosphate and gemcitabine triphosphate).

Elimination Route

Excreted principally in urine as unchanged drug (<10%) and as inactive metabolite.

Half-life

Increases with age.

42, 48, 61, and 79 minutes for men 29, 45, 65, and 79 years of age, respectively.

49, 57, 73, and 94 minutes for women 29, 45, 65, and 79 years of age, respectively.

32–94 minutes following short infusions; 245–638 minutes following long infusions.

Special Populations

Clearance is reduced and half-life increased in women and geriatric patients.

Stability

Storage

Parenteral

Powder for Injection

20–25°C (may be exposed to 15–30°C); do not refrigerate since crystallization may occur.

Solutions are stable for 24 hours at 20–25°C.

Compatibility

Parenteral

Solution CompatibilityHID

Drug Compatibility

Actions

• 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.

• Combined actions of diphosphate and triphosphate metabolites lead to inhibition of DNA synthesis.

• Gemcitabine diphosphate interferes with subsequent de novo nucleotide production by inhibiting ribonucleotide reductase, which is responsible for catalyzing the formation of deoxynucleoside triphosphates needed in DNA synthesis.

• Gemcitabine triphosphate inhibits DNA synthesis by competing with the physiologic substrate, deoxycytidine triphosphate, for DNA polymerase and incorporation into DNA. 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 ε is unable to recognize the abnormal (gemcitabine) nucleotide and repair the DNA strand, which 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.

Advice to Patients

• Risk of myelosuppression. .

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed; necessity for clinicians to advise women to avoid pregnancy.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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