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. |
| Molecular Weight | 299.66 |
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 | Avoid. Embryotoxic and teratogenic in animal studies; may cause fetal harm. |
| 2nd trimester | Avoid. Use only if clearly needed and potential benefit justifies risk; limited human data. |
| 3rd trimester | Avoid. Risk of neonatal bone marrow suppression and other toxicities. |
Clinical note
Other bone marrow suppressants may have additive effects Can cause severe myelosuppression and hemolytic uremic syndrome.
| FDA category | Contraindicated |
| Placental transfer | Gemcitabine crosses the placenta; detected in fetal plasma at concentrations approximately 50-70% of maternal plasma levels. |
| Breastfeeding |
■ 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 |
Hypersensitivity to gemcitabine or any component of the formulationSevere renal impairment (CrCl <30 mL/min) not recommendedConcurrent use with live vaccines
| 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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| Not recommended during breastfeeding. Excretion into human milk unknown, but potential for serious adverse reactions in nursing infants due to cytotoxic properties. |
| Lactation Rating | L5 (Contraindicated) or Avoid |
| 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. |
| 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. |
| Food/Dietary | No specific food interactions. Avoid grapefruit juice if taking concurrent CYP3A4 substrates (e.g., certain statins, immunosuppressants) as gemcitabine may inhibit CYP3A4. |
| Clinical Pearls | Gemcitabine is a nucleoside analog requiring intracellular phosphorylation for activation. Monitor for myelosuppression, particularly thrombocytopenia. Dose reduction may be needed in hepatic impairment. Infusion time longer than 60 minutes increases toxicity. Administer with caution in combination with radiation therapy due to risk of severe pneumonitis. Premedication is not typically required but antiemetics may be given. Monitor for hemolytic uremic syndrome (HUS) and capillary leak syndrome. |
| Patient Advice | Avoid driving or operating machinery if you experience dizziness or fatigue after infusion. · Report any signs of infection, unusual bruising or bleeding, or shortness of breath immediately. · Stay well hydrated to help prevent kidney problems. · Use effective contraception during treatment and for at least 6 months after completion. · Do not receive live vaccines while on this medication. · Inform your doctor if you have ever had liver disease or radiation therapy. |