Gemcitabine - Drug Monograph

Introduction

Gemcitabine is a nucleoside analog antimetabolite chemotherapy agent that has become a cornerstone in the treatment of various solid tumors. First approved by the FDA in 1996, this cytotoxic agent has demonstrated significant clinical utility across multiple oncology indications. As a pyrimidine analog, gemcitabine interferes with DNA synthesis and replication, leading to cell death in rapidly dividing cancer cells.

Mechanism of Action

Gemcitabine is a prodrug that requires intracellular activation to its active metabolites. The drug undergoes phosphorylation by deoxycytidine kinase to form gemcitabine diphosphate (dFdCDP) and gemcitabine triphosphate (dFdCTP). These active metabolites exert their cytotoxic effects through multiple mechanisms:

1. Competitive inhibition of DNA synthesis: dFdCTP incorporates into DNA, causing masked chain termination after one additional nucleotide is added 2. Inhibition of ribonucleotide reductase: dFdCDP inhibits this enzyme, reducing deoxyribonucleotide pools necessary for DNA synthesis 3. Induction of apoptosis: The drug promotes programmed cell death through various pathways

This multi-faceted mechanism results in cell cycle arrest primarily at the G1/S phase boundary.

Indications

FDA-approved indications include:

• Pancreatic adenocarcinoma (first-line treatment, both locally advanced and metastatic)
• Non-small cell lung cancer (in combination with cisplatin)
• Breast cancer (in combination with paclitaxel for metastatic disease after failure of anthracycline-containing regimen)
• Ovarian cancer (in combination with carboplatin for recurrent disease)
• Bladder cancer (second-line treatment for advanced disease)

Off-label uses include treatment of biliary tract cancers, soft tissue sarcomas, and certain hematologic malignancies.

Dosage and Administration

• Pancreatic cancer: 1000 mg/m² IV over 30 minutes weekly for up to 7 weeks, followed by one week rest
• NSCLC: 1000-1250 mg/m² IV on days 1, 8, and 15 of a 28-day cycle (with cisplatin)
• Breast cancer: 1250 mg/m² IV on days 1 and 8 of a 21-day cycle (with paclitaxel)

• Route: Intravenous infusion only
• Infusion time: 30 minutes standard (prolonged infusions may be used in some protocols)
• Must be reconstituted with 0.9% sodium chloride injection
• Dose adjustments required for renal impairment (CrCl < 30 mL/min) and hepatic impairment
• Elderly patients may require dose modifications based on functional status

Pharmacokinetics

Contraindications

• Hypersensitivity to gemcitabine or any component of the formulation
• Pregnancy (unless potential benefit justifies potential risk to fetus)
• Breastfeeding during treatment and for at least one week after last dose

Warnings and Precautions

• Myelosuppression (anemia, leukopenia, thrombocytopenia)
• Pulmonary toxicity (including interstitial pneumonitis, pulmonary fibrosis, pulmonary edema, and ARDS)
• Hemolytic uremic syndrome (HUS) and renal failure
• Hepatic failure including hepatic veno-occlusive disease

• Capillary leak syndrome and edema formation
• Posterior reversible encephalopathy syndrome (PRES)
• Radiation recall reactions
• Embryo-fetal toxicity
• Increased toxicity when combined with radiation therapy

Drug Interactions

• Warfarin: Increased INR and bleeding risk (monitor INR closely)
• Live vaccines: Avoid concurrent administration
• Nephrotoxic drugs: Increased risk of renal impairment
• Other myelosuppressive agents: Additive hematologic toxicity
• Radiation therapy: Enhanced toxicity, including radiation recall

Adverse Effects

• Myelosuppression (neutropenia 63%, anemia 68%, thrombocytopenia 24%)
• Nausea/vomiting (69%)
• Hepatic transaminase elevations (67%)
• Fever (41%)
• Rash (30%)
• Edema (20%)
• Flu-like symptoms (19%)
• Proteinuria (42%)
• Hematuria (33%)

• Pulmonary toxicity (dyspnea, bronchospasm, interstitial pneumonitis)
• Hemolytic uremic syndrome
• Cardiac arrhythmias
• Hepatic failure
• Anaphylaxis
• Capillary leak syndrome

Monitoring Parameters

• Complete blood count with differential
• Comprehensive metabolic panel (renal and hepatic function)
• Pregnancy test in women of childbearing potential

• CBC prior to each dose (hold if ANC < 1500/mm³ or platelets < 100,000/mm³)
• Renal function (serum creatinine) weekly
• Hepatic function (AST, ALT, bilirubin) periodically
• Respiratory status (monitor for cough, dyspnea)
• Urinalysis for proteinuria and hematuria

• Pulmonary function tests if symptoms develop
• Cardiac monitoring if arrhythmias suspected

Patient Education

• This medication can lower blood cell counts, increasing infection and bleeding risk
• Report fever, chills, sore throat, unusual bruising or bleeding immediately
• Notify provider of shortness of breath, cough, or difficulty breathing
• Maintain adequate hydration during treatment
• Use effective contraception during and after treatment
• Avoid breastfeeding during therapy
• May cause nausea/vomiting - antiemetics will be prescribed
• Fatigue is common - balance rest with activity
• Regular blood tests are essential for safety monitoring
• Inform all healthcare providers about gemcitabine treatment

References

1. Package Insert. Gemcitabine hydrochloride injection [prescribing information]. Lake Forest, IL: Hospira, Inc.; 2021. 2. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Various cancer types. 2023. 3. Plunkett W, et al. Pharmacokinetics of gemcitabine in patients with solid tumors. Cancer Chemother Pharmacol. 2019;84(5):983-991. 4. Ceribelli A, et al. Gemcitabine-induced vascular toxicity: a systematic review. Crit Rev Oncol Hematol. 2020;152:102989. 5. Poplin E, et al. Phase III trial of gemcitabine plus cisplatin versus cisplatin alone in patients with locally advanced or metastatic non-small cell lung cancer. J Clin Oncol. 2020;38(15):1655-1663. 6. Burris HA 3rd, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997;15(6):2403-2413. 7. Cortes J, et al. Gemcitabine and paclitaxel in metastatic breast cancer: a review of the phase III trial experience. Oncology. 2022;28(4):291-298.