Gemcitabine
Gemcitabine
Generic Name
Gemcitabine
Mechanism
Gemcitabine (*2’,2’-difluoro-2’-deoxycytidine*) is a deoxycytidine analogue that interferes with DNA synthesis in two principal ways:
• Phosphorylation to Gemcitabine‑5′‑triphosphate (dFdCTP): incorporated into nascent DNA strands, producing chain termination.
• Generation of Gemcitabine‑diphosphate (dFdCDP): inhibits ribonucleotide reductase → decreases deoxynucleotide precursors → further blocks DNA synthesis.
The dual inhibition results in potent cytotoxicity against rapidly proliferating tumour cells.
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Pharmacokinetics
| Parameter | Typical Value | Notes |
| Absorption | *None – intravenous route* | Oral bioavailability ≪10% |
| Distribution | Plasma protein binding ~9 % | Volume of distribution ≈ 1.8 L/m² |
| Metabolism | Primarily deamination by cytidine deaminase (CDA) → 5′‑deoxy‑5‑(fluoromethylene)-1β‑d-ribofuranosyl‑β‑D‑ribofuranosyl‑amine. | Metabolite inactive |
| Elimination | Renal (≈ 60 %) and hepatic (≈ 30 %) | Terminal half‑life 0.3–0.8 h (dFdCTP), 24–48 h overall |
| Clearance | 0.35 L/h/kg (IV) | Dose adjustments recommended for renal impairment (eGFR < 30 mL/min). |
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Indications
- Pancreatic adenocarcinoma (first‑line or adjuvant)
- Non‑small cell lung cancer (NSCLC) (as part of combination therapy: carboplatin + paclitaxel)
- Gallbladder, biliary‑tract, and urothelial cancers
- Breast cancer (combined with capecitabine) – investigational
- Recurrent glioblastoma – off‑label, supported by case series
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Contraindications
- Contraindications
- Known hypersensitivity to gemcitabine or cytidine nucleosides
- Severe neutropenia (ANC < 1 × 10⁹ L⁻¹) or thrombocytopenia (platelets < 75 × 10⁹ L⁻¹)
- Pregnant or lactating women – fetal toxicity
- Warnings
- Myelosuppression – life‑threatening if not monitored
- Infusion‑related reactions: nausea, vomiting, fever, chills
- Renal dysfunction: monitor serum creatinine; dose adjust if eGFR < 30 mL/min
- Cardiotoxicity: rare but serious (arrhythmias, ventricular dysfunction)
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Dosing
| Tumour | Dose | Schedule | Max Duration |
| Pancreatic cancer, NSCLC | Gemcitabine 1000 mg/m² IV | Days 1, 8, 15 of a 28‑day cycle | 6–8 cycles (up to 8 months) |
| Gallbladder, biliary‑tract | 1000 mg/m² | Days 1, 8 of a 21‑day cycle | 6–8 cycles |
| Urothelial carcinoma | 1000 mg/m² | Days 1, 8 of a 21‑day cycle | 6–8 cycles |
| Breast cancer (combo) | 2000 mg/m² | Day 1 only | 6 cycles |
Preparation
• Dilute 50 mg vial in 50 mL 0.9% saline → 50 mg/mL → 1–2 mL per mg.
• Infuse over 30–60 min.
• Use a sterile infusion set; maintain full‑filtration in case of infusion‑related reactions.
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Adverse Effects
- Common (≥10 %)
- Myelosuppression: neutropenia, anemia, thrombocytopenia
- GI: nausea, vomiting, anorexia, stomatitis
- Rash, mild pruritus
- Flu‑like symptoms (fever, chills) during infusion
- Mild hepatotoxicity (elevation of AST/ALT)
- Serious (≤5 %)
- Severe neutropenia → febrile neutropenia
- Progressive pancytopenia
- Cardiotoxicity: arrhythmias, myocardial infarction, acute heart failure (rare)
- Pulmonary toxicity: interstitial pneumonitis
- Severe hypersensitivity reactions including anaphylaxis
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Monitoring
| Parameter | Frequency | Rationale |
| CBC with differential (ANC, Hb, platelets) | Before each cycle and 7–10 days after last dose | Detect early myelosuppression |
| Serum creatinine / eGFR | Baseline, then each cycle | Adjust dose for renal impairment |
| Liver enzymes (AST, ALT, bilirubin) | Baseline, then each cycle | Identify hepatotoxicity |
| ECG (baseline, before dose if cardiac history) | Prior to cycles in patients with CV risk | Monitor for arrhythmia |
| Clinical signs of neutropenic fever | Daily during neutropenia | Prompt empiric antibiotics |
| Fluid balance & electrolytes | Baseline, then each cycle | Prevent electrolyte disturbances |
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Clinical Pearls
- Elderly patients: start at 50 % reduced dose; monitor CBC closely; evidence shows similar efficacy with lower toxicity.
- Cytidine deaminase deficiency: rare but causes prolonged exposure → consider genotyping in refractory cases.
- Combination therapy: avoid simultaneous use of agents that also cause myelosuppression without adequate recovery time; stagger dosing by at least 24 h.
- Infusion reaction mitigation: pre‑medicate with antihistamines (diphenhydramine 25 mg IV) and acetaminophen 650 mg if patient had prior mild reaction.
- Timing with respect to food: Not applicable (IV), but educate staff that no need for fasting.
- Renal dosing algorithm:
- eGFR ≥ 60 mL/min: full dose
- 30–59 mL/min: 75 % dose
- <30 mL/min: 50 % dose or extend interval to every 3 weeks.
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