HYDROXYCHLOROQUINE SULFATE
Clinical safety rating
safeCan cause retinal toxicity requiring regular ophthalmologic exams Can cause retinal toxicity and QT prolongation.
Antimalarial and immunosuppressive agent. Accumulates in lysosomes, raising pH, impairing antigen processing and presentation. Inhibits toll-like receptor signaling and cytokine production (e.g., IL-6, TNF-α). Interferes with quinone reductase activity and heme polymerization in plasmodia.
| Metabolism | Partially metabolized by cytochrome P450 enzymes (CYP2D6, CYP3A4, CYP2C8, CYP2C9) and flavin-containing monooxygenase (FMO). N-desethylation is the major metabolic pathway. |
| Excretion | Renal: ~50% unchanged; Hepatic metabolism: ~50% (desethylchloroquine, desethylhydroxychloroquine); Fecal: minimal (<5%). |
| Half-life | Terminal half-life: ~40–50 days (range 30–60 days) due to extensive tissue distribution. Steady-state reached after 4–6 months. |
| Protein binding | ~50% bound to plasma proteins (albumin). |
| Volume of Distribution | ~800 L/kg (very large, extensive tissue binding, especially melanin-rich tissues). |
| Bioavailability | Oral: ~74% (range 67–91%); Food increases absorption. |
| Onset of Action | Oral: Antimalarial: 2–3 days; Rheumatic disease: 4–12 weeks (slow). |
| Duration of Action | Antimalarial: ~7 days; Rheumatic disease: persists for weeks to months after discontinuation due to long half-life. |
| Molecular Weight | 433.52 Da (as sulfate) |
200-400 mg orally once daily or divided twice daily; maximum 600 mg/day or 6.5 mg/kg/day (whichever is lower). For malaria: 800 mg loading dose, then 400 mg at 6, 24, and 48 hours.
| Dosage form | TABLET |
| Renal impairment | CrCl >=30 mL/min: no adjustment. CrCl <30 mL/min or on dialysis: reduce dose by 50% or extend interval to every 48-72 hours. Not removed by hemodialysis. |
| Liver impairment | Child-Pugh A: no adjustment. Child-Pugh B: reduce dose by 25-50%. Child-Pugh C: contraindicated or use with extreme caution, dose not established. |
| Pediatric use | Malaria: 6.5 mg/kg (base) orally loading dose, then 3.25 mg/kg at 6, 24, 48 hours. Lupus/RA: 3-6.5 mg/kg/day orally once daily; maximum 400 mg/day (or 6.5 mg/kg/day). |
| Geriatric use | No specific dose adjustment but start at low end of dosing range (200 mg orally once daily) due to increased risk of QT prolongation, hypoglycemia, and retinal toxicity. Monitor renal function and cardiac status. |
| 1st trimester | Hydroxychloroquine crosses the placenta. Use only if clearly needed; no increased risk of major malformations reported in systematic reviews. The drug has been used in pregnant patients with SLE and malaria. |
| 2nd trimester | No specific concerns; continued use for chronic conditions like SLE is generally considered acceptable as risks from maternal disease may outweigh fetal risks. |
| 3rd trimester | Use only if benefit outweighs risk; accumulation possible near term due to long half-life. No clear evidence of fetal toxicity at therapeutic doses. |
Clinical note
Can cause retinal toxicity requiring regular ophthalmologic exams Can cause retinal toxicity and QT prolongation.
| FDA category | Human |
| Placental transfer | Hydroxychloroquine crosses the placenta readily with fetal plasma concentrations similar to maternal levels (approximately 90% of maternal concentration) based on cord blood: maternal blood ratios. |
| Breastfeeding | Hydroxychloroquine is excreted into breast milk in small amounts (approximately 2% of maternal weight-adjusted dose). The American Academy of Pediatrics considers it compatible with breastfeeding. Monitor infant for rare adverse effects such as retinal toxicity at recommended doses; however, risk is considered low. |
| Lactation Rating | L2 (Safer) |
| Teratogenic Risk | Hydroxychloroquine is considered low risk for teratogenicity. Studies have not shown an increased risk of major congenital malformations, spontaneous abortion, or fetal death when used at therapeutic doses during pregnancy. There is no evidence of fetal harm from first trimester exposure. Continued use throughout pregnancy is recommended for maternal autoimmune disease management, as disease flares pose greater risk. No specific trimester risks identified. |
| Fetal Monitoring | No specific fetal monitoring is required for hydroxychloroquine use alone. However, baseline and periodic ophthalmologic examinations are recommended for long-term use due to risk of retinal toxicity. For pregnant patients, routine prenatal monitoring is appropriate. In cases of maternal autoimmune disease, additional monitoring for disease activity and fetal well-being (e.g., ultrasound, nonstress tests) may be indicated based on maternal condition. |
| Fertility Effects | Hydroxychloroquine does not appear to adversely affect fertility in women or men. Studies in patients with autoimmune diseases suggest no negative impact on ovarian reserve or sperm parameters. In fact, by controlling autoimmune disease activity, hydroxychloroquine may improve fertility outcomes in affected individuals. |
■ FDA Black Box Warning
Hydroxychloroquine can cause retinal toxicity (irreversible retinopathy) with prolonged use. Dose-related and cumulative. Baseline and annual ophthalmic examinations are mandatory. Risk increased with daily dose >5.0 mg/kg actual body weight, cumulative dose >1000 grams, and concomitant use of tamoxifen.
| Common Effects | lupus |
| Serious Effects |
History of hypersensitivity to 4-aminoquinoline compoundsPre-existing retinopathy of any etiologyUse in patients with known retinal or visual field changes unless benefit clearly outweighs riskG6PD deficiency (relative; absolute if hemolysis risk)
| Precautions | Retinopathy: irreversible, dose and duration dependent. Monitor with fundoscopy, visual fields, spectral-domain optical coherence tomography (SD-OCT)., Cardiotoxicity: cardiomyopathy, conduction disorders (e.g., QT prolongation, torsades de pointes). Avoid with other QT-prolonging drugs., Hypoglycemia: can cause severe hypoglycemia, especially in diabetic patients., Neuropsychiatric effects: agitation, psychosis, suicidal ideation., Hematologic toxicity: agranulocytosis, aplastic anemia (rare)., Neuromuscular toxicity: vacuolar myopathy, neuropathy., Drug interactions: CYP2D6 inhibitors (e.g., fluoxetine) may increase levels. Caution with antidiabetic agents., Pregnancy: Use only if clearly needed; crosses placenta., Hepatic/renal impairment: dose adjustment may be required. |
| Food/Dietary | No significant food interactions. May be taken with food to improve tolerability. Avoid grapefruit juice? Not reported for hydroxychloroquine specifically (grapefruit affects CYP3A4 but hydroxychloroquine is not primarily metabolized by CYP3A4). No dietary restrictions. |
| Clinical Pearls | Hydroxychloroquine has a long half-life (40-50 days); loading doses may achieve steady state faster but increase retinal toxicity risk. Annual ophthalmologic screening is mandatory after 5 years of use or earlier if risk factors (e.g., cumulative dose >1000g, renal disease, tamoxifen use). Monitor for QTc prolongation, especially when combined with other QT-prolonging drugs. Consider baseline G6PD testing in patients with hemolytic anemia risk. May cause hypoglycemia; monitor blood glucose in diabetics. |
| Patient Advice | Take with food or milk to reduce gastrointestinal upset. · Do not double doses if missed; take as soon as remembered unless near next dose. · Report any vision changes (blurring, difficulty reading, light sensitivity) immediately. · Avoid alcohol as it may increase liver toxicity risk. · Inform your doctor of all medications (especially digoxin, antiepileptics, QT-prolonging drugs). · May cause dizziness; avoid driving until you know how it affects you. · Complete annual eye exams even if no vision problems. · Do not stop suddenly without consulting physician. |
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