Gemzar - Drug Monograph

Introduction

Gemzar (gemcitabine hydrochloride) is a nucleoside analog antineoplastic agent widely used in oncology practice. First approved by the FDA in 1996, this chemotherapy medication has become a cornerstone in the treatment of various solid tumors. As a pyrimidine analog, Gemzar interferes with DNA synthesis and replication, ultimately leading to apoptotic cell death in rapidly dividing cancer cells.

Mechanism of Action

Gemzar exerts its cytotoxic effects through multiple mechanisms. After intracellular activation to diphosphate (dFdCDP) and triphosphate (dFdCTP) metabolites, it:

• Competes with deoxycytidine triphosphate for incorporation into DNA
• Inhibits DNA polymerase and ribonucleotide reductase
• Causes masked chain termination after incorporation into DNA (where one additional nucleotide is added after gemcitabine incorporation)
• Induces apoptosis through activation of caspase pathways

This multi-faceted mechanism results in synergistic cytotoxic effects and makes Gemzar effective against various cancer cell types.

Indications

FDA-approved indications include:

• First-line treatment of locally advanced or metastatic pancreatic adenocarcinoma
• First-line treatment of locally advanced or metastatic non-small cell lung cancer (in combination with cisplatin)
• Metastatic breast cancer (in combination with paclitaxel, after failure of anthracycline-containing regimen)
• Advanced ovarian cancer (in combination with carboplatin, after relapse至少6 months after platinum-based therapy)
• Bladder cancer (second-line treatment for advanced disease after platinum-based therapy failure)

Off-label uses include treatment of biliary tract cancers, cervical cancer, and soft tissue sarcomas.

Dosage and Administration

• Pancreatic cancer: 1000 mg/m² IV over 30 minutes weekly for up to 7 weeks, followed by one week rest
• Non-small cell lung cancer: 1000-1250 mg/m² IV on days 1, 8, and 15 of each 28-day cycle (with cisplatin)
• Other cancers: Various regimens based on specific protocols

• Route: Intravenous infusion only
• Standard concentration: 10 mg/mL or 40 mg/mL solutions
• Infusion time: 30 minutes (prolonged infusion times increase toxicity)
• Dose adjustments required for renal impairment (CrCl < 30 mL/min) and hematologic toxicity

• Elderly: No specific dose adjustment, but increased monitoring recommended
• Renal impairment: Reduce dose for CrCl < 30 mL/min
• Hepatic impairment: Use with caution; no specific guidelines

Pharmacokinetics

Contraindications

• Hypersensitivity to gemcitabine or any component of formulation
• Pregnancy (unless potential benefit justifies potential fetal risk)
• Breastfeeding
• Severe renal impairment (CrCl < 30 mL/min) without dose adjustment

Warnings and Precautions

• Myelosuppression: Monitor blood counts regularly; may require dose modification or delay
• Pulmonary toxicity: Can cause severe pulmonary events including pulmonary edema, interstitial pneumonitis, and ARDS
• Hemolytic uremic syndrome (HUS): Monitor for microangiopathic hemolysis
• Hepatic toxicity: May cause elevations in transaminases; monitor liver function
• Capillary leak syndrome: Monitor for edema and hypotension
• Embryo-fetal toxicity: Can cause fetal harm; effective contraception required
• Radiation recall: Can cause severe skin reactions in previously irradiated areas
• Extravasation injury: Can cause severe tissue damage; ensure proper IV placement

Drug Interactions

• Live vaccines: Avoid concurrent administration
• Warfarin: Increased INR and bleeding risk; monitor closely
• Other myelosuppressive agents: Additive hematologic toxicity
• Nephrotoxic drugs: May reduce gemcitabine clearance
• Radiotherapy: Enhanced toxic effects, especially esophagitis and pneumonitis

Adverse Effects

• Myelosuppression (anemia, neutropenia, thrombocytopenia)
• Nausea/vomiting (mild to moderate)
• Fatigue
• Transaminase elevation
• Fever
• Rash
• Edema

• Hematuria
• Proteinuria
• Dyspnea
• Alopecia
• Diarrhea
• Constipation

• Hemolytic uremic syndrome
• Acute respiratory distress syndrome
• Capillary leak syndrome
• Severe skin reactions
• Anaphylaxis
• Cardiac arrhythmias

Monitoring Parameters

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

• CBC before each dose (monitor for myelosuppression)
• Liver function tests regularly
• Renal function assessment
• Signs/symptoms of pulmonary toxicity
• Monitoring for hemolytic uremic syndrome (LDH, haptoglobin, schistocytes)
• Fluid status and blood pressure

• Periodic assessment of renal function
• Monitoring for late effects in survivors

Patient Education

• Importance of regular blood tests and monitoring
• Signs of infection (fever, chills) requiring immediate medical attention
• Potential for fatigue and need for adequate rest
• Nausea management strategies
• Contraception requirements during and after treatment
• Avoidance of live vaccines
• Reporting any new or worsening symptoms promptly:

- Shortness of breath or cough - Unusual bleeding or bruising - Swelling or weight gain - Yellowing of skin or eyes

• Importance of hydration but awareness of fluid retention
• Hair thinning or loss possible
• Potential impact on fertility

References

1. Gemzar® (gemcitabine HCl) prescribing information. Eli Lilly and Company, 2023. 2. National Comprehensive Cancer Network (NCCN) Guidelines. Various cancer sites, 2023. 3. Plunkett W, et al. Gemcitabine: metabolism, mechanisms of action, and self-potentiation. Semin Oncol. 1995;22(4 Suppl 11):3-10. 4. Hertel LW, et al. Evaluation of the antitumor activity of gemcitabine. Cancer Res. 1990;50(14):4417-4422. 5. Burris HA 3rd, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer. J Clin Oncol. 1997;15(6):2403-2413. 6. Anderson H, et al. Gemcitabine: a review of its pharmacology and clinical potential in non-small cell lung cancer and pancreatic cancer. Drugs. 1994;48(1):66-90. 7. ClinicalTrials.gov database for current treatment protocols and ongoing research. 8. Micromedex® DrugDex® evaluations. IBM Watson Health, 2023. 9. UpToDate® drug information. Wolters Kluwer, 2023. 10. American Society of Clinical Oncology (ASCO) guidelines for various cancer types.