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Online calculator for hydroxychloroquine dosing

Published:February 18, 2020DOI:https://doi.org/10.1016/j.jcjo.2020.01.002
      Hydroxychloroquine (HCQ), or Plaquenil, is a mainstay therapy for rheumatoid arthritis, systemic lupus erythematosus, and other autoimmune and dermatological conditions.
      • Marmor M.F.
      • Kellner U.
      • Lai T.Y.
      • Melles R.B.
      • Mieler W.F.
      American Academy of Ophthalmology: recommendations on screening for chloroquine and hydroxychloroquine retinopathy (2016 revision).
      In 2016, an estimated 4.9 million prescriptions for HCQ were written in North America. Although HCQ is one of the safest disease-modifying antirheumatic drugs with minimal systemic effects, chronic use has been linked to irreversible retinopathy in a daily and cumulative dose-dependent manner by body weight. Clinical signs of HCQ-related retinal toxicity range from maculopathy with retinal pigment epithelium (RPE) changes to advanced retinopathy with bull's eye maculopathy characterized by a ring of parafoveal RPE depigmentation.
      • Marmor M.F.
      • Kellner U.
      • Lai T.Y.
      • Melles R.B.
      • Mieler W.F.
      American Academy of Ophthalmology: recommendations on screening for chloroquine and hydroxychloroquine retinopathy (2016 revision).
      Other findings include central vision loss, decreased colour vision, central scotomas, photopsia, and visual field deficits.
      The Royal College of Ophthalmologists and the American Academy of Ophthalmology (AAO) previously recommended HCQ dosing of <6.5 mg/kg/day of ideal body weight to mitigate the risk of retinopathy. Nevertheless, research demonstrated a prevalence rate of HCQ retinopathy of 7.5% (n = 2361) over 5 years among patients following these older guidelines.
      • Marmor M.F.
      • Kellner U.
      • Lai T.Y.
      • Melles R.B.
      • Mieler W.F.
      American Academy of Ophthalmology: recommendations on screening for chloroquine and hydroxychloroquine retinopathy (2016 revision).
      Moreover, decreased renal function, concurrent tamoxifen therapy for breast cancer, and pre-existing retinal or macular disease are documented risk factors and markedly increase the risk of retinal toxicity.
      • Marmor M.F.
      • Kellner U.
      • Lai T.Y.
      • Melles R.B.
      • Mieler W.F.
      American Academy of Ophthalmology: recommendations on screening for chloroquine and hydroxychloroquine retinopathy (2016 revision).
      As a result, the AAO revised its guidelines in 2016 to decrease the maximum dosage to 5 mg/kg/day of real body weight to minimize retinal toxicity. Despite this recommendation, some clinicians are not following the guidelines and continue to prescribe 400 mg daily.
      • Zoler M.L.
      Hydroxychloroquine dosing recommendations often ignored.
      The National Resource Center on Lupus also continues to list the old dosage of 6.5 mg/kg/day. These findings are unsurprising considering that, after the last guideline revision in 2011, it was shown that implementation and adherence to even the older guidelines were poor among rheumatologists and ophthalmologists. In a U.K.-based study, approximately 10% of patients in rheumatology clinics were prescribed HCQ doses exceeding recommendations after accounting for actual body weight and renal function.
      • Worth C.
      • Yusuf I.H.
      • Turner B.
      • et al.
      An audit of the use of hydroxychloroquine in rheumatology clinics.
      To aid in the ophthalmic monitoring for HCQ toxicity, we developed an online calculator (https://tinyurl.com/yxzhwg4u) that provides a suggested weekly dosing schedule based on a patient's weight and risk factors for HCQ retinopathy. With the weekly regimens, in some cases, the daily dose may exceed the 5 mg/kg/day limit, but the weekly dose does not exceed 35 mg/kg/week. Blood levels of HCQ are reported to stabilize over many weeks, so that variable dosing will average out over time.
      • Marmor M.F.
      • Kellner U.
      • Lai T.Y.
      • Melles R.B.
      • Mieler W.F.
      American Academy of Ophthalmology: recommendations on screening for chloroquine and hydroxychloroquine retinopathy (2016 revision).
      The AAO and Royal College of Ophthalmologists clinical practice guidelines, the product monographs, relevant literature, and available calculators for HCQ dosing were reviewed using PubMed, MEDLINE, and Google Scholar. Variations of the following natural language terminology were used in our search strategy: hydroxychloroquine, Plaquenil, dosing, retinal toxicity, and retinopathy. A consultation was conducted with 4 academic rheumatologists and 4 pharmacists in the Greater Toronto Area to understand the general culture of prescribing HCQ.
      Some Plaquenil monographs
      • Shulman S.
      • Wollman J.
      • Brikman S.
      • Padova H.
      • Elkayam O.
      • Paran D.
      Implementation of recommendations for the screening of hydroxychloroquine retinopathy: poor adherence of rheumatologists and ophthalmologists.
      suggest that the film-coated tablets should not be crushed or divided, which limits prescribing regimens to a 200-mg tablet dosing schedule. However, on consultation with academic rheumatologists and pharmacists in the Greater Toronto Area, it appears that a non-film-coated generic HCQ pill can be cut in half for optimal dosing regimens, and as such, our calculator provides an alternative dosing regimen with 100 mg increments as well. Incremental dosing by 100 mg allows for increased dosing accuracy by weight and may be safer for patients at higher risk of retinal toxicity, including pediatric patients and patients with renal impairment and retinal disease, or those requiring concurrent tamoxifen therapy.
      Although other calculators are available, they do not provide a tablet-based dosing schedule or consider the patient risk factors listed in the 2016 AAO Revised Guidelines. Additionally, although the excretory patterns of HCQ are not well characterized, its metabolites are slowly excreted through the renal system.
      • Ashley C.
      • Currie A.
      The Renal Drug Handbook.
      Unique to HCQ dosing calculators, our online calculator provides a dosing schedule for patients with decreased creatinine clearance and considers the pediatric population.
      Current recommendations suggest that patients prescribed HCQ should undergo a baseline ophthalmic examination upon initiation of therapy. Baseline screening requires fundus examination to exclude pre-existing retinal or optic nerve damage, with central 10-2 visual field testing (central 10-2 for non-Asian patients and central 24-2 or 30-2 for Asian patients) and spectral-domain optical coherence tomography if there is an indication of pre-existing macular disease or optic neuropathy. Multifocal electroretinogram and fundus autofluorescence are other possible screening tests. Colour vision testing and fluorescein angiography were not recommended as screening tests.
      • Marmor M.F.
      • Kellner U.
      • Lai T.Y.
      • Melles R.B.
      • Mieler W.F.
      American Academy of Ophthalmology: recommendations on screening for chloroquine and hydroxychloroquine retinopathy (2016 revision).
      Annual screening is recommended for after 5 years of use and sooner if there are major risk factors. If there is no pre-existing maculopathy or other risk factors for HCQ use, patients can use 5 mg/kg/day of HCQ, with reassessment after 5 years of HCQ use. However, with long-term use, there may not be a single dose of HCQ that can entirely mitigate the risk of retinopathy while effectively treating the patient's disease. In patients with daily consumption of 4.0–5.0 mg/kg of HCQ retinopathy occurred at a prevalence rate of less than 2% during the first 10 years of use, but escalated to approximately 20% after 20 years of use. As such, patients should be educated and counselled on the risks of HCQ-related toxicity, the importance of scheduled dosing regimens, the implications of weight loss or change in renal function, and the need for ophthalmic monitoring.

      Footnotes and Disclosure

      We acknowledge and thank Mr. Rikin Patel for his technical contributions and assistance in the creation of the presented online calculator.
      None of the authors have commercial associations, financial relationships, or conflicts of interest relevant to this article for disclosure.

      Appendix. Supplementary materials

      References

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