Chloroquine and Hydroxychloroquine Toxicity

Updated: Mar 15, 2019
  • Author: Manolette R Roque, MD, MBA, FPAO; Chief Editor: Andrew G Lee, MD  more...
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Practice Essentials

Chloroquine and hydroxychloroquine belong to the quinolone family. Although their therapeutic and toxic doses differ, they are related drugs with similar clinical indications for use and similar manifestations of retinal toxicity. The image below depicts hydroxychloroquine retinopathy.

Fluorescein angiogram of left macula in patient wi Fluorescein angiogram of left macula in patient with hydroxychloroquine retinopathy. Reprinted from American Journal of Ophthalmology, Vol 104, Johnson and Vine, Hydroxychloroquine therapy in massive total doses without retinal toxicity, pages 139-144, Copyright 1987, with permission from Elsevier Science.

Signs and symptoms

Retinopathy may be asymptomatic or may cause central or paracentral scotomas leading to difficulty reading or performing fine visual tasks (due to parafoveal metamorphopsia). Visual acuity usually remains intact until advanced disease.

Other reported visual symptoms include the following:

  • Dimness
  • Flickering or flashing lights of yellow
  • Green or red haloes
  • Cycloplegia
  • Amblyopia
  • Diplopia
  • Blindness
  • Photophobia
  • Oculogyric crisis

Systemic complaints include the following:

  • Nausea, abdominal pain, and vomiting
  • Occasionally, skin conditions, such as rashes, pruritus, and sensitivity to ultraviolet light
  • Rarely, neurologic symptoms, such as vertigo, tinnitus, irritability, cranial nerve palsies, and myasthenialike muscle weakness

Findings on eye examination include the following:

  • Corneal deposits
  • Posterior subcapsular lens opacity (chloroquine)
  • Irregularity in the macular pigmentation and blunting of the foveal reflex (early)
  • Bull’s eye maculopathy (classic finding in non-Asian patients)
  • Peripheral pigment irregularity and bone spicule formation, vascular attenuation, and optic disc pallor (end stage)

See Clinical Presentation for more detail.


Patients starting treatment with chloroquine/hydroxychloroquine should have a baseline examination by an ophthalmologist that includes the following:

  • History (including refraction)
  • Visual acuity (uncorrected visual acuity [UCVA] and best spectacle-corrected visual acuity [BSCVA])
  • Slit-lamp biomicroscopy
  • Direct and indirect ophthalmoscopy (this is not a screening tool, as it reveals relatively late toxic changes)

The examination should also include a Humphrey visual field central 10-2 white-on-white pattern (24-2 or 30-2 in Asian patients) and at least one of the following objective tests, if available (see Workup):

  • Spectral domain optical coherence tomography (SD-OCT)
  • Fundus autofluorescence (FAF) test
  • Multifocal electroretinogram (mfERG)

Ancillary tests used in the diagnosis of toxicity include the following:

  • Amsler grid
  • Color vision testing
  • Color fundus photography: documenting changes over time, especially in patients with preexisting retinal pathology
  • Full-field ERG or electro-oculogram
  • Fluorescein angiography: may assist in visualizing early subtle changes in the retinal pigment epithelium

See Workup for more detail.


Withdrawal of the medication and shifting to another treatment is the standard of care. Coordination with the rheumatologist or the dermatologist may be warranted for comprehensive care of the patient. No diet or medical therapy has been proven effective to prevent, treat, or reduce risk of retinal toxicity.

See Treatment and Medication for more detail.



Chloroquine and hydroxychloroquine belong to the quinolone family. Although their therapeutic and toxic doses differ, they are related drugs with similar clinical indications for use and similar manifestations of retinal toxicity.

Initially, chloroquine was given for malaria prophylaxis and treatment. Subsequently, it was used by rheumatologists for treating rheumatoid arthritis, systemic/discoid lupus erythematosus, and other connective tissue disorders. Dermatologists use these drugs for cutaneous lupus. Expanded use of these drugs for nonmalarial disease entities has resulted in prolonged duration of therapy and higher daily dosages than those used in antimalarial therapy.

Hydroxychloroquine has largely replaced chloroquine in the United States, except among patients who travel to areas endemic with malaria. Although the mechanisms of the two agents are presumed to be the same, many reports suggest that chloroquine is more toxic to the retina than hydroxychloroquine. The toxic dosage for chloroquine was derived from hydroxychloroquine retinal toxicity studies, although no definitive data have shown pharmacologic equivalence. [1]

The first reports of retinal toxicity attributed to chloroquine appeared during the late 1950s. In 1958, Cambiaggi first described the classic retinal pigment changes in a patient receiving chloroquine for systemic lupus erythematous (SLE). In 1959, Hobbs established a link between long-term use of chloroquine and subsequent development of retinal pathology. In 1962, J Lawton Smith coined the term bull's eye maculopathy, regarded as the classic finding of macular toxicity.

Physicians who prescribe chloroquine and hydroxychloroquine may not be fully aware of the potential ophthalmic implications. In the management of patients treated with these agents, the preferred practice is regular screening. Patients and referring physicians should understand that screening helps to identify toxicity early but cannot guarantee prevention of toxicity and vision loss.



The mechanism of chloroquine and hydroxychloroquine toxicity is not well understood. Chloroquine has an affinity for pigmented (melanin-containing) structures, which may explain its toxic properties in the eye. Melanin serves as a free-radical stabilizer and can bind toxins, including retinotoxic drugs. However, it is unclear whether this binding effect is beneficial or harmful.

Chloroquine and its principal metabolite accumulate in pigmented ocular structures at concentrations higher than other tissues and withdraws more slowly relative to other tissues upon withdrawal of therapy. [2, 3] Prolonged exposure can allow the drug to accumulate in the retina, where it remains in the pigmented structures long after its use is stopped. In patients with retinopathy, traces of chloroquine have been found in plasma, erythrocytes, and urine 5 years or more after discontinuation of the drug. [4] However, progression of retinopathy after discontinuation of therapy may not result from slow clearance but gradual decompensation of cells injured during drug therapy. [1]



Chloroquine/hydroxychloroquine retinopathy is influenced most by daily dose, length of use, and cumulative dose. The kinetics of chloroquine metabolism are complex, with the half-life increasing with increasing dosage.

Factors associated with hydroxychloroquine toxicity include the following:

  • Maintenance dose greater than 5 mg/kg/d based on real weight (most critical risk)
  • Daily dose greater than 400 mg
  • Cumulative dose greater than 1000 g
  • Age older than 60 years

Factors associated with chloroquine toxicity include the following:

  • Maintenance dose greater than 2.3 mg/kg/d
  • Obesity

Factors associated with toxicity in both drugs include the following:

  • Duration of treatment greater than 5 years (critical factor)
  • Tamoxifen use (5-fold risk)
  • Evidence of renal insufficiency
  • Underlying retinal disease or maculopathy (macular degeneration)
  • Evidence of liver disease
  • P450 polymorphisms leading to higher drug concentration in blood

A study of chloroquine/hydroxychloroquine retinopathy in a Turkish cohort found no significant difference between affected and unaffected patients with respect to several risk factors. Rather, the cumulative dose of hydroxychloroquine was significantly higher in the unaffected patients. These findings suggest that the currently widely accepted risk factors may not be applicable to all patients and that there may be risk factors previously not reported that may play a role in the development of toxicity. [5]



Despite variability of statistics in published reports, a consistent trend found in the literature is that the incidence of retinopathy from chloroquine/hydroxychloroquine increases with both the daily dose and the duration of treatment. The risk of developing retinal toxicity is less than 2% in patients who use dosages below the recommended threshold for up to 10 years. The risk increases significantly after 20 years of therapy and/or daily dose above the recommended threshold. [6]

Older patients are believed to be at a higher risk because of the higher rate of retinal comorbidities.



If the maximum daily dosage recommendations are followed, the likelihood of toxicity from chloroquine or hydroxychloroquine is less than 1% the first five years of treatment. [1] Corneal epithelial changes are usually reversible, but retinopathy caused by these agents are not. If diagnosed early, before RPE damage, there is mild and limited progression of the disease upon discontinuation of the agents. Once the appearance of a bull's eye maculopathy is noted, which indicates advanced stage of toxicity, disease progression can continue for years after discontinuation of the agents. Risk to vision and disease progression are a function of disease severity at the time of detection. [7, 8]


Patient Education

When starting patients on chloroquine or hydroxychloroquine, clinicians should counsel patients about the benefits and limitations of screening. Patients should be informed that screening can detect toxicity at early stages and limit progression of vision loss but cannot necessarily prevent all toxicity and associated vision risk.

Advise patients to consult their physician and an ophthalmologist if changes in visual acuity or if blurred vision occurs while on treatment, as risk of vision loss may warrant discontinuation of the medication.