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. |
| Molecular Weight | 252.19 Da |
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 | Avoid. Hydroxyurea is teratogenic in animal studies; human data limited. Use only if benefit outweighs risk. |
| 2nd trimester | Avoid unless essential; monitor fetal growth. May cause fetal abnormalities. |
| 3rd trimester | Avoid unless essential; risk of neonatal bone marrow suppression. |
Clinical note
Comprehensive clinical and safety monograph for SIKLOS (SIKLOS).
| Placental transfer | Crosses placenta in humans and animals; documented placental transfer with potential fetal harm. |
| Breastfeeding | Excreted in breast milk; potential for serious adverse effects in nursing infants. Discontinue breastfeeding or avoid drug. |
| Lactation Rating |
■ 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 |
Severe bone marrow suppressionHypersensitivity to hydroxyurea
| 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 |
| Food/Dietary | Grapefruit and grapefruit juice increase drug levels; avoid concurrent use. High-fat meals may enhance absorption; take with food to reduce gastrointestinal upset. |
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| L5 (Contraindicated) |
| 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 | 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. |
| Clinical Pearls | For sickle cell disease patients: monitor hemoglobin and reticulocyte count periodically. Dose titration based on weight is critical; do not exceed 10 mg/kg/day. Avoid use in patients with severe renal impairment (CrCl <30 mL/min). May cause hemolysis in G6PD deficiency. |
| Patient Advice | Take this medication exactly as prescribed, usually twice daily with food. · Do not crush or chew tablets; swallow whole. · Drink plenty of water to prevent dehydration, which can worsen sickle cell crises. · Seek medical attention if you experience worsening pain, severe fatigue, or jaundice. · Inform your doctor if you have liver or kidney problems. · Avoid grapefruit or grapefruit juice while taking this medication. |