Hydroxychloroquine

Hydroxychloroquine is a 4-aminoquinoline antimalarial used as a long-term immunomodulator in systemic lupus erythematosus, rheumatoid arthritis, Sjogren disease and antiphospholipid syndrome. It is not immunosuppressive in the usual sense and does not raise infection risk meaningfully, which makes it the base drug in lupus.

Class. Antimalarial 4-aminoquinoline, conventional synthetic disease-modifying anti-rheumatic drug.

Mechanism. It accumulates in lysosomes and raises their pH, interfering with antigen processing and major histocompatibility complex class II presentation, and blocks endosomal toll-like receptor 7 and 9 signalling, reducing interferon and cytokine production.

Pharmacokinetics. Oral absorption is about 75 percent. It is widely distributed and concentrates in melanin-rich tissue such as the retina. The terminal half-life is 40 to 50 days, so benefit takes 3 to 6 months and persists after stopping. Elimination is partly renal.

Systemic lupus erythematosus (all patients unless contraindicated).

• Dose: 200 to 400 mg daily, orally, in one or two doses with food.

• Maximum dose: 5 mg/kg/day actual body weight (so a 50 kg patient takes at most 250 mg daily).

• Loading dose: none.

• Titration: start at the target weight-based dose; reduce to the lowest effective dose after sustained remission.

• Duration: indefinite. Stopping raises flare risk.

Rheumatoid arthritis (mild disease or combination). 200 to 400 mg daily, not over 5 mg/kg/day. Onset is slow, and it is often combined with methotrexate and sulfasalazine.

Sjogren disease, antiphospholipid syndrome, palindromic rheumatism, cutaneous lupus and discoid lupus. Same dose ceiling of 5 mg/kg/day.

Malaria (note for East Africa). Chloroquine-resistant Plasmodium falciparum is widespread, so hydroxychloroquine is not used for treatment or prophylaxis of falciparum malaria in the region. Where parasites are susceptible: prophylaxis 400 mg once weekly starting 1 to 2 weeks before exposure and continuing for 4 weeks afterwards; treatment 800 mg then 400 mg at 6, 24 and 48 hours.

Contraindications. Pre-existing maculopathy, known hypersensitivity to 4-aminoquinolines, and uncorrected prolonged QT interval or serious ventricular arrhythmia risk.

Boxed-warning-level risks. Irreversible retinal toxicity (dose and duration related), cardiomyopathy and conduction disorder with chronic use, QT prolongation and torsades de pointes, severe hypoglycaemia, and acute fatal toxicity in overdose.

Adverse effects. Common: nausea, diarrhoea, abdominal cramps, headache, skin rash and hyperpigmentation. Serious: bull's-eye maculopathy, skeletal and cardiac myopathy, neuropsychiatric effects, haemolysis in G6PD deficiency (uncommon), agranulocytosis and severe cutaneous reactions.

Major interactions. QT-prolonging drugs (macrolides, fluoroquinolones, ondansetron, antipsychotics, methadone), insulin and sulphonylureas (hypoglycaemia), digoxin and ciclosporin (raised levels), antacids and kaolin (separate by 4 hours), tamoxifen (additive retinal risk), antiepileptics (reduced seizure threshold).

Common prescribing errors. Exceeding 5 mg/kg/day of actual body weight; not adjusting for renal impairment; omitting retinal screening.

Special groups.

• Pregnancy: continue in lupus and rheumatoid arthritis. It lowers flare and congenital heart block risk and is not teratogenic at therapeutic doses.

• Breastfeeding: compatible at usual doses.

• Children: 5 mg/kg/day or less, with fixed tablet fractions; keep out of reach because a single ingestion in a toddler can be lethal.

• Older adults: lower end of the dose range; check QT and renal function.

• Kidney impairment: eGFR under 30 mL/min, reduce dose (often 200 mg daily or about 25 percent lower) and screen the retina more often.

• Liver impairment: use with caution; no fixed adjustment.

Formulations. 200 mg film-coated tablets taken with food or milk, swallowed whole.

Baseline. Retinal examination within the first year (optical coherence tomography and visual fields), electrocardiogram if other QT-prolonging drugs are used or cardiac disease is present, creatinine and eGFR, G6PD status where available, and weight.

Monitoring. Annual retinal screening after 5 years of therapy, starting earlier (after 1 year) and annually with a dose over 5 mg/kg, eGFR under 60 mL/min, concurrent tamoxifen, or pre-existing macular disease. Weight and renal function at least yearly. Electrocardiogram if new QT-prolonging drugs are added.

Stop thresholds. Any suspected retinal toxicity, new visual field or colour vision change, or myopathy or cardiomyopathy. Stop and refer.

Overdose. Cardiotoxicity and hypokalaemia appear within 1 to 3 hours. Manage in a resuscitation setting with airway protection, activated charcoal if early, correction of potassium, magnesium and sodium bicarbonate for wide QRS, with high dose diazepam and adrenaline infusion under specialist toxicology advice.

Referral and escalation. Refer to ophthalmology for any visual symptom or screening abnormality, and to a rheumatologist for non-response at 6 months.