Clinical safety rating
safeHuman studies have proved safety
Hydroxychloroquine is a 4-aminoquinoline antimalarial agent that accumulates in lysosomes and inhibits Toll-like receptor signaling, reduces cytokine production, and interferes with antigen presentation. It also inhibits heme polymerase in malarial parasites, leading to toxic heme accumulation.
| Metabolism | Primarily metabolized by CYP2D6, CYP3A4, and CYP2C8; also undergoes N-dealkylation. |
| Excretion | Primarily renal (30-60% unchanged); minor hepatic metabolism; fecal elimination accounts for ~20-30%. |
| Half-life | Terminal half-life: 30-60 days (prolonged due to extensive tissue binding); clinical context: requires loading dose for rapid effect. |
| Protein binding | 30-50% bound to plasma proteins (albumin). |
| Volume of Distribution | 5,000-18,000 L/kg (extensive tissue distribution, particularly in melanin-containing tissues). |
| Bioavailability | Oral: ~74% (range 60-80%). |
| Onset of Action | Oral: 1-3 months for rheumatoid arthritis; 2-4 weeks for malaria prophylaxis. |
| Duration of Action | Prolonged (weeks to months) due to slow elimination; accumulation with chronic dosing. |
| Molecular Weight | 335.87 |
400 mg orally once daily or 200 mg orally twice daily, then 200-400 mg orally once daily for maintenance, depending on indication.
| Renal impairment | CrCl <10 mL/min: reduce dose by 50%; CrCl <30 mL/min: use with caution; not dialyzable. |
| Liver impairment | Child-Pugh class C (severe impairment): reduce dose by 50%; Child-Pugh class A or B: no adjustment recommended. |
| Pediatric use | 6.5 mg/kg base (not to exceed 400 mg) orally once daily; for lupus erythematosus, 3-5 mg/kg per day. |
| Geriatric use | No specific adjustment required; monitor for QT prolongation and retinal toxicity due to age-related decreased renal function and longer half-life. |
| 1st trimester | Use only if benefit outweighs risk; associated with increased risk of miscarriage and malformations in animal studies; limited human data suggest possible increased risk of congenital anomalies. |
| 2nd trimester | Use with caution; may be used for autoimmune diseases if clearly needed; monitor for maternal and fetal effects. |
| 3rd trimester | Use with caution; no known teratogenic effects in late pregnancy; risk of neonatal hypoglycemia if used near term. |
Clinical note
Safe and recommended to continue throughout pregnancy in women with systemic lupus erythematosus (SLE) and other rheumatological conditions. Discontinuation of hydroxychloroquine in SLE during pregnancy leads to disease flares, which carry significant fetal risk. Long-term safety data in lupus pregnancies (PROMISSE study and others) is reassuring. Crosses the placenta but no structural teratogenicity demonstrated. Protects against SLE-related pregnancy complications including preeclampsia and preterm birth.
| Placental transfer | Crosses placenta readily with fetal concentrations similar to maternal; active transport via placental efflux transporters. |
| Breastfeeding | Excreted into breast milk in low amounts; levels insufficient to cause adverse effects in infants; American Academy of Pediatrics considers compatible with breastfeeding. |
| Lactation Rating | L2 (Probably Compatible) |
| Teratogenic Risk | Hydroxychloroquine is not associated with increased risk of major congenital malformations when used at standard doses for autoimmune diseases during pregnancy. First trimester exposure does not elevate teratogenic risk beyond baseline. Second and third trimester use has been associated with potential risk of retinopathy in the infant if high doses are used, but this is rare at therapeutic doses. No specific fetal toxicities have been consistently demonstrated. |
| Fetal Monitoring | Monitor for maternal retinal toxicity with baseline and periodic ophthalmologic exams. No specific fetal monitoring required beyond standard prenatal care, but consider growth ultrasound if high doses are used long-term. |
| Fertility Effects | Hydroxychloroquine is not known to impair fertility. In patients with autoimmune diseases, it may improve fertility by controlling disease activity. |
■ FDA Black Box Warning
Hydroxychloroquine can cause serious cardiac adverse events, including QT prolongation, torsades de pointes, and sudden cardiac death, especially when used with other QT-prolonging drugs or in patients with risk factors. It may also cause severe hypoglycemia, including loss of consciousness, which can be life-threatening.
| Serious Effects |
Hypersensitivity to hydroxychloroquine or 4-aminoquinoline compoundsPre-existing retinopathy of any etiologyKnown glucose-6-phosphate dehydrogenase (G6PD) deficiency (relative, caution)
| Precautions | Cardiac effects (QT prolongation, cardiomyopathy), hypoglycemia, retinopathy (irreversible), neuropsychiatric effects (psychosis, suicidal thoughts), hematologic toxicity (agranulocytosis, aplastic anemia), hepatic impairment, renal impairment, and exacerbation of psoriasis or porphyria. |
| Food/Dietary | Take with food or milk to minimize gastrointestinal irritation. Avoid grapefruit juice as it may increase drug levels (CYP3A4 inhibition). No significant interactions with other foods, but consistent timing with meals helps adherence. |
| Clinical Pearls | Hydroxychloroquine has a long half-life (40-50 days), so steady state takes months. Retinal toxicity is dose-dependent and cumulative; screen with baseline fundoscopy, visual fields, and spectral-domain OCT, then annually after 5 years or earlier with risk factors (e.g., renal disease, tamoxifen use). Maximum daily dose should not exceed 5.0 mg/kg real body weight to reduce retinopathy risk. Avoid in G6PD deficiency due to hemolytic anemia risk. QT prolongation possible, especially with concomitant QT-prolonging drugs or electrolyte disturbances. Onset of action for RA/SLE is 4-12 weeks. Drug accumulates in melanin-rich tissues, causing retinal binding. |
| Patient Advice | Take with food or milk to reduce stomach upset. · Do not stop suddenly; long-term use requires regular eye exams before starting and annually after 5 years. · Report any vision changes (blurring, difficulty reading, light sensitivity) immediately. · Avoid alcohol to reduce risk of liver toxicity. · Seek medical help if you develop rash, easy bruising, or signs of infection (fever, sore throat). · Do not use during pregnancy unless benefit outweighs risk; use effective contraception. · Store at room temperature away from moisture and heat. |
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