SIKLOS
Clinical safety rating: caution
Comprehensive clinical and safety monograph for SIKLOS (SIKLOS).
Hydroxyurea inhibits ribonucleotide reductase, reducing the synthesis of deoxyribonucleotides and thereby decreasing DNA synthesis. In sickle cell disease, it increases fetal hemoglobin (HbF) levels, which inhibits sickling of red blood cells.
| Metabolism | Hydroxyurea is primarily metabolized by the liver via the urea cycle and nitric oxide pathway, with partial renal elimination. |
| Excretion | Primarily hepatic metabolism via CYP3A4; renal excretion of metabolites accounts for approximately 70-80% of the dose, with <1% excreted unchanged in urine. Fecal excretion is minor (<5%). |
| Half-life | Terminal elimination half-life is 2-5 hours in adults; shorter in children (1-2 hours). Clinical context: requires thrice-daily dosing to maintain therapeutic concentrations; longer half-life in hepatic impairment (up to 10 hours). |
| Protein binding | Approximately 30-50% bound to plasma proteins, primarily albumin and to a lesser extent α1-acid glycoprotein. |
| Volume of Distribution | Apparent volume of distribution is 0.5-1.0 L/kg, indicating distribution into total body water and some tissue binding; higher Vd in children (1.2 L/kg). |
| Bioavailability | Oral bioavailability is 50-70% due to first-pass metabolism; food does not significantly affect absorption. No other routes of administration. |
| Onset of Action | Oral: 1-2 hours for initial clinical effect (reduction in sickle cell crisis frequency); peak effect in 4-8 weeks. |
| Duration of Action | Duration is 8-12 hours after oral administration; clinical effect (reduced vaso-occlusive crises) persists with continuous dosing; no prolonged duration beyond dosing interval. |
100–200 mg/kg/day orally in two divided doses, not to exceed 200 mg/kg/day.
| Dosage form | TABLET |
| Renal impairment | No specific adjustment required; monitor renal function due to potential nephrotoxicity. |
| Liver impairment | No specific adjustment for mild-moderate impairment; severe impairment: consider dose reduction and monitor. |
| Pediatric use | Weight-based: initial 100 mg/kg/day divided twice daily; titrate to 200 mg/kg/day maximum. |
| Geriatric use | No specific dose adjustment; monitor renal function and volume status, start at low end of dose range. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for SIKLOS (SIKLOS).
| Breastfeeding | No data on presence in human milk; M/P ratio unknown. Due to potential for serious adverse reactions (e.g., hemolytic anemia), breastfeeding is not recommended during therapy and for 2 weeks after last dose. |
| Teratogenic Risk | FDA Pregnancy Category C. First trimester: No adequate human studies; animal studies show embryo-fetal toxicity at doses ≥100 mg/kg/day (2.5 times MRHD). Second/third trimester: Potential for fetal anemia, decreased fetal hemoglobin; use only if benefit outweighs risk. |
| Fetal Monitoring |
■ FDA Black Box Warning
Hydroxyurea is carcinogenic in animals and has been reported to be leukemogenic in humans. Monitor complete blood counts closely.
| Serious Effects |
["Hypersensitivity to hydroxyurea","Severe bone marrow suppression (e.g., severe anemia, leukopenia, thrombocytopenia)","Pregnancy (category D) due to teratogenicity","Breastfeeding (excreted in human milk)"]
| Precautions | ["Bone marrow suppression (anemia, leukopenia, thrombocytopenia); monitor CBCs regularly","Carcinogenicity and mutagenicity; avoid use during pregnancy and lactation","Increased risk of pancreatitis, hepatotoxicity, and severe skin reactions (including cutaneous vasculitis)","Renal impairment may require dose adjustment"] |
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| Baseline and periodic CBC (weekly for first 2 months, then every 2 weeks), Reticulocyte count, hemoglobin, bilirubin, LDH (hemolysis markers). Fetal monitoring: serial ultrasound for growth restriction and anemia; consider Doppler assessment for fetal anemia. |
| Fertility Effects | No human studies. In animal studies, no effects on fertility at doses up to 60 mg/kg/day in rats (0.9 times MRHD). Potential for ovarian suppression or impaired spermatogenesis at high doses; clinical significance unknown. |