GEMCITABINE
Clinical safety rating: avoid
Contraindicated (not allowed)
Gemcitabine is a nucleoside analog (2',2'-difluorodeoxycytidine) that is phosphorylated intracellularly to active diphosphate (dFdCDP) and triphosphate (dFdCTP) metabolites. dFdCDP inhibits ribonucleotide reductase, reducing deoxynucleotide pools for DNA synthesis. dFdCTP competes with deoxycytidine triphosphate for incorporation into DNA, causing masked chain termination and inhibiting DNA polymerase and repair.
| Metabolism | Gemcitabine is extensively metabolized intracellularly by deoxycytidine kinase (dCK) to monophosphate (dFdCMP), then by other kinases to active di- and triphosphates. Inactivated by cytidine deaminase (CDA) to 2',2'-difluorodeoxyuridine (dFdU), which is renally excreted. |
| Excretion | Primarily renal: ~92-98% of the dose excreted in urine, with <10% as unchanged gemcitabine and the majority as the inactive metabolite 2',2'-difluorodeoxyuridine (dFdU). Fecal excretion is minimal (<1%). |
| Half-life | Terminal elimination half-life for gemcitabine is 42-94 minutes (mean ~57 min) in plasma; for its metabolite dFdU, the half-life is 14-74 hours (mean ~40 h), which accumulates with repeated dosing and may contribute to prolonged systemic exposure. |
| Protein binding | Negligible; gemcitabine is <10% bound to plasma proteins. dFdU is also minimally bound. |
| Volume of Distribution | Volume of distribution for gemcitabine is 0.5-0.8 L/kg (approximately 50 L for a 70 kg adult), indicating distribution into total body water. For dFdU, Vd is about 0.15-0.2 L/kg, suggesting limited tissue penetration. |
| Bioavailability | Intravenous only (100% bioavailability). Oral bioavailability is <5% due to extensive first-pass metabolism, and not clinically used. |
| Onset of Action | Intravenous administration: Onset of antitumor effect is not immediate; clinical response typically observed after several weeks of therapy. For radiosensitization, effect occurs within hours of infusion. |
| Duration of Action | Duration of antitumor effect is variable and schedule-dependent; the drug is typically administered weekly for 3 weeks followed by a 1-week rest. Myelosuppression may last 7-14 days after infusion. |
| Molecular Weight | 299.66 |
1000-1250 mg/m² intravenously over 30 minutes on days 1 and 8 of a 21-day cycle.
| Dosage form | INJECTABLE |
| Renal impairment | For CrCl 30-80 mL/min: no adjustment; for CrCl <30 mL/min: use with caution at reduced dose; for CrCl <10 mL/min: not recommended. |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: reduce dose by 25%; Child-Pugh C: not recommended. |
| Pediatric use | Not established; safety and efficacy not determined. |
| Geriatric use | No specific dose adjustment; monitor renal function and hematologic toxicity closely. |
| 1st trimester | Contraindicated: teratogenic in animal studies; avoid use during first trimester unless clearly necessary. |
| 2nd trimester | Use only if potential benefit justifies risk to fetus; embryotoxic and fetotoxic in animal models. |
| 3rd trimester | Use only if potential benefit justifies risk; risk of fetal myelosuppression and other toxicities. |
Clinical note
Other bone marrow suppressants may have additive effects Can cause severe myelosuppression and hemolytic uremic syndrome.
| Placental transfer | Crosses placenta in animal studies; likely crosses human placenta based on molecular weight and properties. |
| Breastfeeding | Not recommended during breastfeeding due to potential for serious adverse reactions in nursing infants. Excretion into human milk is unknown; however, based on molecular weight and animal data, it is likely present. |
■ FDA Black Box Warning
Gemcitabine can cause serious and sometimes fatal adverse effects including: hemolytic uremic syndrome (HUS), capillary leak syndrome (CLS), posterior reversible encephalopathy syndrome (PRES), pulmonary toxicity (pneumonitis, pulmonary edema), and severe myelosuppression (neutropenia, thrombocytopenia).
| Common Effects | other cancers |
| Serious Effects |
Hypersensitivity to gemcitabine or any excipientsSevere bone marrow suppressionConcurrent live vaccines
| Precautions | Myelosuppression (neutropenia, thrombocytopenia, anemia): Monitor blood counts., Pulmonary toxicity (interstitial pneumonitis, pulmonary edema, ARDS): Discontinue if severe., Hemolytic uremic syndrome (HUS): Discontinue if microangiopathic hemolytic anemia, thrombocytopenia, renal failure., Capillary leak syndrome (CLS): Monitor for edema, hypotension, hemoconcentration., Posterior reversible encephalopathy syndrome (PRES): Monitor for hypertension, seizures, headache, visual disturbances., Hepatotoxicity: Monitor liver function., Renal toxicity: Monitor renal function., Fetal harm: Advise pregnant women of risk., Radiation toxicity: Increased toxicity when given with radiation therapy. |
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| Lactation Rating | L5 (Contraindicated) |
| Teratogenic Risk | Pregnancy category D. First trimester: Potential for teratogenicity (malformations, embryotoxicity) based on animal studies and its mechanism of action (antimetabolite). Second and third trimesters: Risk of fetal growth restriction, oligohydramnios, and neonatal myelosuppression. Avoid use unless maternal benefit outweighs fetal risk. |
| Fetal Monitoring | Maternal: Complete blood count with differential (baseline and before each dose), hepatic (ALT, AST, bilirubin), and renal function (serum creatinine). Fetal: Ultrasound for growth, amniotic fluid volume, and morphology if exposed in second/third trimester; serial growth scans if continued use. |
| Fertility Effects | May cause irreversible gonadal suppression in both sexes. In males, oligospermia or azoospermia; in females, amenorrhea, ovarian failure, and reduced fertility potential. Pre-treatment fertility preservation counseling advised. |
| Food/Dietary | No specific food interactions. Avoid grapefruit juice if taking concurrent CYP3A4 substrates. Maintain adequate hydration. |
| Clinical Pearls | Gemcitabine requires dose adjustment for renal impairment (CrCl <30 mL/min). Infusion times >60 minutes increase toxicity without improving efficacy (dose-rate effect). Monitor for hemolytic uremic syndrome (HUS) and pulmonary toxicity. Premedication for nausea is recommended. B12 and folate supplementation reduce hematologic toxicity. |
| Patient Advice | Take B12 injections and folic acid as prescribed to reduce side effects. · Report any shortness of breath, swelling of legs, or blood in urine immediately. · Avoid pregnancy; use effective contraception during and for 6 months after treatment. · Stay hydrated and avoid aspirin or NSAIDs to reduce bleeding risk. · Contact your doctor if you develop fever, chills, or signs of infection. |