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Chloroquine and Hydroxychloroquine Toxicity Treatment & Management

  • Author: Manolette R Roque, MD, MBA, FPAO; Chief Editor: Hampton Roy, Sr, MD  more...
 
Updated: Nov 03, 2015
 

Approach Considerations

Withdrawal of the medication and shifting to another form of treatment is the standard of care. Coordination with the rheumatologist or the dermatologist is warranted for comprehensive care of the patient.

If serious toxic symptoms occur from overdosage or sensitivity, it has been suggested that ammonium chloride (8 g daily in divided doses for adults) be administered orally 3-4 times/wk for several months after therapy has been stopped. Acidification of the urine with ammonium chloride increases renal excretion of the 4-aminoquinoline compounds by 20-90%. In patients with impaired renal function and/or metabolic acidosis, caution must be taken.

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Deterrence/Prevention

During therapy, patients should be monitored on an annual basis. The clinician should record any visual symptoms, visual acuity, and fundus examination results. After 5 years of treatment, annual screenings should include an ocular examination, 10-2 threshold field testing, and one of the objective tests (ie, SD-OCT, mfERG, fundus autofluorescence).

Ophthalmologists should know the latest guidelines. Ophthalmologists are held to the position on hydroxychloroquine by the American Academy of Ophthalmology.

The most important factor in avoiding toxicity with long-term therapy appears to be the daily dose. If the daily dose is below the stated threshold levels, then the chance of encountering any retinopathy is small. However, it is essential that the clinician discuss the early symptoms of toxicity with the patient. A high index of suspicion of toxicity would justify the performance of expensive ancillary procedures to detect possible retinopathy.

It is important to understand that at the present time, no criterion standard exists for identification of the ocular toxicity prior to its clinical manifestation. This has led to controversy regarding the recommendations for ophthalmologic examinations for screening patients on hydroxychloroquine. Current guidelines need to be improved to prevent permanent retinopathy from these medications.

The recommended safe threshold dose has been reported as 3.5 mg/kg/d for chloroquine and 6.5 mg/kg/d for hydroxychloroquine. These dosages are based on lean body weight. A body mass index calculator used by endocrinologists is helpful in calculating the recommended dose.

The standard ideal weight, which factors in height, is calculated as follows:

  • For women, the ideal weight is 100 lb for 5 feet, plus 5 lb per extra inch of height.
  • For men, the ideal weight is 110 lb for 5 feet, plus 5 lb per extra inch of height.
  • Note: 1 kg = 2.2 lb

In addition, pediatric and elderly patients should be considered at high risk for toxicity and should be monitored closely. Dose adjustments should be made in patients with renal impairment or hepatic insufficiency.

The National Registry of Drug-Induced Ocular Side Effects is a resource for soliciting information about, and contributing reports of, suspected drug toxicities. To access the Registry, go to www.eyedrugregistry.com. The service is free, although American Academy of Ophthalmology membership is required for entry.

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Long-Term Monitoring

A yearly visual field examination is useful to detect changes from hydroxychloroquine. Multifocal ERG assessment is a required element in the preferred practice pattern of patients treated with antimalarial agents. Whenever abnormalities are noted, additional testing should be obtained. Humphrey visual field central 10-2 white-on-white pattern should be repeated promptly if central or parafoveal changes are seen, even if these appear to be nonspecific. If the findings are reproducible, objective testing should be repeatedly performed.

If toxicity is suspected, more frequent and detailed examinations should be conducted. Once toxicity is confirmed, the prescribing physician should be informed and hydroxychloroquine therapy should be discontinued unless it is medically critical and the patient has been informed of the visual risk.

Once retinal toxicity is identified, the drug is discontinued and other immunosuppressive agents are substituted. Chloroquine and/or hydroxychloroquine clear very slowly from the body, so the full effects may not manifest for 3-6 months. Slow, continued deterioration of visual function may occur even after the drug is discontinued.

A small case series study revealed evidence of retinal toxicity that included difficulty with reading, variation in fundus findings from normal to bull’s eye maculopathy, electroretinogram (ERG) findings of reduced rod and cone function, and abnormal visual fields. Cessation of the study drug did not result in sustained improved visual function: 6 of 16 patients had progressive loss of retinal function despite cessation of the study drug.[8]

The authors recommend that patients be reevaluated 3 months after a diagnosis of toxicity is made, even after discontinuation of drug use. Annual examinations are recommended until the findings have clearly stabilized.

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Contributor Information and Disclosures
Author

Manolette R Roque, MD, MBA, FPAO Section Chief, Ocular Immunology and Uveitis, Department of Ophthalmology, Asian Hospital and Medical Center; Section Chief, Ocular Immunology and Uveitis, International Eye Institute, St Luke's Medical Center Global City; Senior Eye Surgeon, The LASIK Surgery Clinic; Director, AMC Eye Center, Alabang Medical Center

Manolette R Roque, MD, MBA, FPAO is a member of the following medical societies: American Academy of Ophthalmology, American Society of Cataract and Refractive Surgery, Philippine Medical Association, American Uveitis Society, International Ocular Inflammation Society, Philippine Ocular Inflammation Society, American Society of Ophthalmic Administrators, American Academy of Ophthalmic Executives, Philippine Society of Cataract and Refractive Surgery

Disclosure: Nothing to disclose.

Coauthor(s)

C Stephen Foster, MD, FACS, FACR, FAAO, FARVO Clinical Professor of Ophthalmology, Harvard Medical School; Consulting Staff, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary; Founder and President, Ocular Immunology and Uveitis Foundation, Massachusetts Eye Research and Surgery Institution

C Stephen Foster, MD, FACS, FACR, FAAO, FARVO is a member of the following medical societies: Alpha Omega Alpha, American Academy of Ophthalmology, American Association of Immunologists, American College of Rheumatology, American College of Surgeons, American Federation for Clinical Research, American Medical Association, American Society for Microbiology, American Uveitis Society, Association for Research in Vision and Ophthalmology, Massachusetts Medical Society, Royal Society of Medicine, Sigma Xi

Disclosure: Nothing to disclose.

Barbara L Roque, MD, DPBO, FPAO Senior Partner, Roque Eye Clinic; Chief of Service, Pediatric Ophthalmology and Strabismus Section, Department of Ophthalmology, Asian Hospital and Medical Center; Active Consultant Staff, International Eye Institute, St Luke's Medical Center Global City

Barbara L Roque, MD, DPBO, FPAO is a member of the following medical societies: American Academy of Ophthalmology, American Association for Pediatric Ophthalmology and Strabismus, American Society of Cataract and Refractive Surgery, Philippine Society of Cataract and Refractive Surgery, Philippine Academy of Ophthalmology, Philippine Society of Pediatric Ophthalmolo

Disclosure: Nothing to disclose.

Chief Editor

Hampton Roy, Sr, MD Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences

Hampton Roy, Sr, MD is a member of the following medical societies: American Academy of Ophthalmology, American College of Surgeons, Pan-American Association of Ophthalmology

Disclosure: Nothing to disclose.

Acknowledgements

Harold H Harsch, MD Program Director of Geropsychiatry, Department of Geriatrics/Gerontology, Associate Professor, Department of Psychiatry and Department of Medicine, Froedtert Hospital, Medical College of Wisconsin

Harold H Harsch, MD is a member of the following medical societies: American Psychiatric Association

Disclosure: lilly Honoraria Speaking and teaching; Forest Labs None None; Pfizer Grant/research funds Speaking and teaching; Northstar None None; Novartis Grant/research funds research; Pfizer Honoraria Speaking and teaching; Sunovion Speaking and teaching; Otsuke Grant/research funds reseach; GlaxoSmithKline Grant/research funds research; Merck Honoraria Speaking and teaching

Alan D Schmetzer, MD Professor Emeritus, Interim Chairman, Vice-Chair for Education, Associate Residency Training Director in General Psychiatry, Fellowship Training Director in Addiction Psychiatry, Department of Psychiatry, Indiana University School of Medicine; Addiction Psychiatrist, Midtown Mental Health Cener at Wishard Health Services

Alan D Schmetzer, MD is a member of the following medical societies: American Academy of Addiction Psychiatry, American Academy of Clinical Psychiatrists, American Academy of Psychiatry and the Law, American College of Physician Executives, American Medical Association, American Neuropsychiatric Association, American Psychiatric Association, and Association for Convulsive Therapy

Disclosure: Eli Lilly & Co. Grant/research funds Other

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

References
  1. Yaylali SA, Sadigov F, Erbil H, Ekinci A, Akcakaya AA. Chloroquine and hydroxychloroquine retinopathy-related risk factors in a Turkish cohort. Int Ophthalmol. 2013 Mar 2. [Medline].

  2. Bernstein HN. Chloroquine ocular toxicity. Surv Ophthalmol. 1967 Oct. 12(5):415-47. [Medline].

  3. [Guideline] Hansen MS, Schuman SG. Hydroxychloroquine-Induced Retinal Toxicity. American Academy of Ophthalmology. Available at http://www.aao.org/publications/eyenet/201106/pearls.cfm?RenderForPrint=1&. Accessed: April 23, 2013.

  4. [Guideline] Karmel M. Rx Side Effects: New Plaquenil Guidelines and More. American Academy of Ophthalmology. Available at http://www.aao.org/aao/publications/eyenet/201105/retina1.cfm?RenderForPrint=1&. Accessed: April 23, 2013.

  5. Cukras C, Huynh N, Vitale S, Wong WT, Ferris FL 3rd, Sieving PA. Subjective and objective screening tests for hydroxychloroquine toxicity. Ophthalmology. 2015 Feb. 122 (2):356-66. [Medline].

  6. Anderson C, Pahk P, Blaha GR, Spindel GP, Alster Y, Rafaeli O, et al. Preferential Hyperacuity Perimetry to detect hydroxychloroquine retinal toxicity. Retina. 2009 Sep. 29(8):1188-92. [Medline].

  7. Angi M, Romano V, Valldeperas X, Romano F, Romano MR. Macular sensitivity changes for detection of chloroquine toxicity in asymptomatic patient. Int Ophthalmol. 2009 Jan 23. [Medline].

  8. Michaelides M, Stover NB, Francis PJ, Weleber RG. Retinal toxicity associated with hydroxychloroquine and chloroquine: risk factors, screening, and progression despite cessation of therapy. Arch Ophthalmol. 2011 Jan. 129(1):30-9. [Medline].

 
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A 53-year-old female with a complaint of something "funny" with her vision. The possibility of hydroxychloroquine toxicity was entertained, although clinical evidence was not found. Color vision testing and funduscopic examination were normal. A full field electroretinogram was normal, but foveal cone electroretinograms were reduced bilaterally. These findings prompted the question of possible early hydroxychloroquine retinopathy.
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.
Membranous cytoplasmic bodies in ganglion cell of retina. (N=nucleus) (X12,500.) Reprinted from American Journal of Ophthalmology, Vol 67, Gleiser CA, Dukes TW, Lawwill T, Read WK, Bay WW, Brown RS. Ocular changes in swine associated with chloroquine toxicity, pages 399-405, Copyright 1969, with permission from Elsevier Science.
Swollen ganglion cells with foamy cytoplasm (Hematoxylin-eosin, X500). Reprinted from American Journal of Ophthalmology, Vol 67, Gleiser CA, Dukes TW, Lawwill T, Read WK, Bay WW, Brown RS. Ocular changes in swine associated with chloroquine toxicity, pages 399-405, Copyright 1969, with permission from Elsevier Science.
The same patient as described in the image above (other eye, left eye). The patient (with foveal cone electroretinogram reduction) had abnormal computerized acuity mapping of the macula results.
An Amsler grid is used to assess the central portion of the macula. This simple test is helpful for patients to monitor their vision at home.
 
 
 
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