GEMCITABINE HYDROCHLORIDE
Clinical safety rating: avoid
Other bone marrow suppressants may have additive effects Can cause severe myelosuppression and hemolytic uremic syndrome.
Gemcitabine is a nucleoside analog that inhibits DNA synthesis. It is phosphorylated intracellularly to active diphosphate and triphosphate metabolites. The diphosphate inhibits ribonucleotide reductase, reducing deoxynucleotide pools, while the triphosphate competes with deoxycytidine triphosphate for incorporation into DNA, causing masked chain termination and apoptosis.
| Metabolism | Gemcitabine is primarily metabolized intracellularly by deoxycytidine kinase (to active monophosphate form), and further to diphosphate and triphosphate metabolites. Inactivation occurs via cytidine deaminase (to difluorodeoxyuridine) primarily in the liver, kidney, and blood. Less than 10% of the drug is excreted unchanged in urine. |
| Excretion | Primarily renal: 92-98% of administered dose excreted unchanged in urine; <1% excreted in feces; <5% as inactive metabolite 2',2'-difluorodeoxyuridine. |
| Half-life | Short terminal half-life (~8-17 min) for parent drug; prolonged 14-18 h for triphosphate active metabolite intracellularly in peripheral blood mononuclear cells; clinical context necessitates prolonged infusion schedules. |
| Protein binding | <10% bound; negligible binding to albumin or alpha-1-acid glycoprotein. |
| Volume of Distribution | Central Vd ~50 L/m² (approx 0.7 L/kg for 70 kg adult); extensive tissue distribution; intracellular accumulation in cancer cells. |
| Bioavailability | Not administered orally (bioavailability <10% due to extensive first-pass metabolism); clinically given only IV; mean steady-state concentration 10-50 μM. |
| Onset of Action | IV infusion: Clinical effect (myelosuppression) observed within 1-2 weeks; antineoplastic activity requires intracellular activation and is not immediate. |
| Duration of Action | Duration of myelosuppression: 7-14 days; clinical response in NSCLC observed after 2-3 cycles (weeks); gemcitabine triphosphate retention intracellularly extends effect. |
1000 mg/m² IV over 30 minutes on days 1 and 8 of a 21-day cycle, or 1250 mg/m² IV 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: contraindicated. Monitor renal function closely. Hold gemcitabine if CrCl <30 mL/min. Consider alternative therapy. For patients with end-stage renal disease on hemodialysis, use is not recommended. |
| Liver impairment | Child-Pugh A: no adjustment. Child-Pugh B: reduce dose to 800 mg/m² IV on days 1 and 8 of a 21-day cycle. Child-Pugh C: avoid use. Monitor liver function tests. |
| Pediatric use | 1000 mg/m² IV over 30 minutes on days 1 and 8 of a 21-day cycle. Safety and efficacy not established in children <18 years. |
| Geriatric use | No specific dose adjustment based on age alone. Monitor renal function and hematologic toxicity closely. Consider starting at lower end of dosing range (1000 mg/m²) and titrate based on tolerance. Age >65 years may increase risk of myelosuppression. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Other bone marrow suppressants may have additive effects Can cause severe myelosuppression and hemolytic uremic syndrome.
| FDA category | Contraindicated |
| Breastfeeding | Excreted in breast milk; M/P ratio unknown. Due to risk of severe neonatal myelosuppression, discontinue nursing or drug. Advised to pump and discard milk for at least 7 days after last dose. |
| Teratogenic Risk | Pregnancy Category D. First trimester: Malformations (limb defects, neural tube defects) and spontaneous abortion risk. Second/third trimester: Fetal myelosuppression, growth restriction, and possibly preterm labor. Avoid use in pregnancy unless benefit outweighs risk. |
■ FDA Black Box Warning
Gemcitabine can cause severe myelosuppression, including neutropenia, thrombocytopenia, and anemia. Patients should be monitored for bone marrow suppression before each dose. Prolonged infusion times (>60 minutes) have been associated with increased toxicity, including hepatic and hematologic effects. Gemcitabine is contraindicated in patients with known hypersensitivity to the drug.
| Common Effects | other cancers |
| Serious Effects |
["Known hypersensitivity to gemcitabine or any component of the formulation","Severe bone marrow suppression (e.g., absolute neutrophil count <500/mm³ or platelets <50,000/mm³) prior to initiating therapy"]
| Precautions | ["Myelosuppression: Dose-limiting neutropenia, thrombocytopenia, and anemia; monitor CBCs before each dose.","Pulmonary toxicity: Interstitial pneumonitis, pulmonary fibrosis; discontinue if unexplained dyspnea or pulmonary infiltrates develop.","Hepatic toxicity: Elevation of transaminases; use caution in patients with hepatic impairment.","Renal toxicity: Hemolytic uremic syndrome (HUS) with renal failure; discontinue if microangiopathic hemolytic anemia, thrombocytopenia, or renal impairment occurs.","Cardiovascular: Case reports of myocardial infarction, arrhythmias, and heart failure.","Radiation toxicity: Exacerbation of radiation-induced toxicity (e.g., skin, lung) if given concurrently or within 7 days.","Capillary leak syndrome: Rare but severe; discontinue if signs develop (e.g., edema, hypotension).","Fertility: May cause irreversible infertility."] |
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| Fetal Monitoring | Complete blood counts weekly during pregnancy. Fetal growth ultrasound every 4-6 weeks. Amniotic fluid index monitoring if prolonged exposure. Consider fetal echocardiography due to cardiotoxicity potential. |
| Fertility Effects | May cause ovarian failure (premature menopause) in females and azoospermia in males. Reversible after discontinuation in some cases. Advise fertility preservation before chemotherapy. |