Hydroxychloroquine dosing

Corneal deposits during the long-term treatment of RA are not uncommon but the most prominent concern is the danger of producing irreversible retinal damage. At the usual antirheumatic doses these risks seem to be less for hydroxychloroquine than for chloroquine. 

Hydroxychloroquine is approved for the treatment of both systemic and cutaneous lupus erythematosus. Both chloroquine and quinacrine (Atabrine) are also effective in this skin disease. Low-dose chloroquine is used for the therapy of porphyria cutanea tarda in patients in whom phlebotomy has failed or is contraindicated. Other skin diseases in which the drugs are useful (after sunscreens and avoidance of sun exposure) include polymorphous light eruption and solar urticaria. 

Antimalarials are approved for rheumatoid arthritis, but they are not considered very effective DMARDs. Dose-response and serum concentration-response relationships have been documented for hydroxychloroquine and dose-loading may increase rate of response. 

Petersen CS, Thomsen K. High-dose hydroxychloroquine treatment of porphyria cutanea tarda. J Am Acad Dermatol 1992 26(4) 614-9. 

Marmor MF. Hydroxychloroquine at the recommended dose (< or = 6.5 mg/kg/day) is safe for the retina in patients with rheumatoid arthritis and systemic lupus erythematosus. Clin Exp Rheumatol. 2004 22 143-144. 

Antimalarials are approved for rheumatoid arthritis, but they are not considered very efficacious DMARDs. Dose-response and serum concentration-response relationships have been documented for hydroxychloroquine. While antimalarials improve symptoms, there is no evidence that these compounds alter bony damage in rheumatoid arthritis at their usual dosages (up to 6.4 mg/kg/d hydroxychloroquine or 200 mg/d chloroquine). It usually takes 3-6 months to obtain a response. Antimalarials are often used for the treatment of the skin manifestations, serositis, and joint pains of... 

The pharmacology of these drugs, which are also used in the treatment of malaria, is presented on p. 351. The mechanism of their anti-inflammatory activity is uncertain. Besides inhibiting nucleic acid synthesis, they are known to stabilize lysosomal membranes and trap free radicals. In treating inflammatory disorders, they are reserved for rheumatoid arthritis that has been unresponsive to the NSAIDs or else they are used in conjunction with an NSAID, which allows a lower dose of chloroquine or hydroxychloroquine to be administered. These drugs have been shown to slow progression of erosive bone lesions and may induce remission. They do cause serious adverse effects (see p. 351). 

Dose. For an acute attack of malaria, 2 g of hydroxychloroquine sulphate given over three days (1.2 g on the first dayX In rheumatoid arthritis, initially 400 to 800 mg daily. 

After an oral dose of hydroxychloroquine sulphate equivalent to 310 mg of the base to 6 subjects, peak plasma concentrations of 0.003 to 0.20 pg/ ml (mean 0.08) were attained in 3 hours. Following oral administration of hydroxychloroquine diphosphate equivalent to 1264 mg of the base to... 

Long-term chloroquine can cause cardiac comphca-tions, such as conduction disorders and cardiomyopathy (restrictive or hypertrophic), by structural alteration of the interventricular septum (4). Thirteen cases of cardiac toxicity associated with long-term chloroquine and hydroxychloroquine have been reported in patients with systemic autoimmune diseases. The cumulative doses were 600-2281 g for chloroquine and 292-4380 g for hydroxychloroquine. 

A 39-year-old woman with rheumatoid arthritis took hydroxychloroquine 200 mg bd for painful synovitis, in addition to meloxicam, co-dydramol, and Gaviscon. She inadvertently took twice the prescribed dose of hydroxychloroquine, but stopped it after 2 weeks because of nausea. The next day she developed a widespread blotchy erythema and 2 weeks later was admitted to hospital with clinical and histological toxic epidermal necrolysis and deteriorated rapidly with multiorgan failure she died 1 week later. 

Susceptibihty factors have been investigated in a large retrospective study of 274 patients aged under 45 years, of whom 70 had received cyclophosphamide, 84 azathiopr-ine but not cyclophosphamide, and 88 either no drug or hydroxychloroquine alone (35). The overall incidence of ovarian failure, defined as sustained amenorrhea for at least 12 months and documented by reduced estradiol concentrations, was 26, 1, and 0% respectively. The mean delay to onset of the first missed menses was 4.4 months. A higher age at the start of treatment and cumulative dose were independent risk factors for cyclophosphamide-induced ovarian failure. The incidences were 14, 28, and 50% in patients aged under 30 years, 30-39 years, and over 40 years respectively, and 4, 26, 31, 70%... 

Hydroxychloroquine. In most ways, hydroxychloroquine (Plaquenil) parallels chloroquinc. Structurally, it differs solely in having a hydroxy moiety on one of the /V-cIhyl groups. Like chloroquinc. it remains in Ihc body for over a month, and prophylactic dosing is once weekly. The otha indications, both FDA approved and off-label, arc very. similar. 

Dosage and duration of therapy depend on patient response, tolerance of side effects, and development of retinal toxicity, which is a potentially irreversible adverse reaction associated with long-term therapy, especially with chloroquine. Current recommended doses of antimalarials in SLE are hydroxychloroquine 200-400 mg/day and chloroquine 250-500 mg/day. After 1 or 2 years of treatment, gradual tapering of dosage can be attempted. Some patients may require only one or two tablets per week to suppress cutaneous manifestations. ... 

Side effects of these drugs include CNS effects (e.g., headache, nervousness, insomnia, and others), rashes, dermatitis, pigmentary changes of the skin and hair, gastrointestinal disturbance (e.g., nausea), and reversible ocular toxicities such as cycloplegia and corneal deposits. Potentially serions retinal toxicity is uncommon when the currently recommended doses are used and is least common with hydroxychloroquine. However, because of the possibility of permanent damage associated with the retinopathy, an ophthalmologic evaluation should be done at baseline and every 3 months when chloroquine is used and every 6 to 12 months when hydroxychloroquine is used. If retinal abnormalities are noted, antimalarial therapy should be discontinued or the dose reduced. ... 

In rat adjuvant arthritis Newbould found that neither chloroquine nor hydroxychloroquine is effective , despite the fact that radioactive material was detected in the inflamed joints of adjuvant treated rats dosed with C chloroquine phosphate . 

Irreversible retinopathy and ototoxicity can result from high daily doses (>250 mg) of chloro-quine or hydroxychloroquine that lead to cumulative total doses of more than 1 g of base per kilogram body weight, such as those used for treatment of diseases other than malaria. Retinopathy can be avoided if the daily dose is 50 mg. Prolonged therapy with high doses of 4-aminoquinoline also can cause toxic myopathy, cardiopathy, and peripheral neuropathy these reactions improve if the drug is withdrawn promptly. Rarely, neuropsychiatric disturbances, including suicide, may be related to overdose. 

Usual doses of antimalarials are hydroxychloroquine, 200 mg twice a day chloroquine, 250-500 mg/day and quinacrine, 100-200 mg/day. Usually, hydroxychloroquine is started first, and if no improvement is noted in 3 months, quinacrine is added. Alternatively, chloroquine is used as a single agent. Dosing should be adjusted for low-weight individuals so that chloroquine dosing is 2.5 mg/kg/day and hydroxychloroquine is 6.5 mg/kg/day. Antimalarial agents are the treatment of choice for widespread forms of cutaneous lupus that do not respond to topical glucocorticoids and sunscreens. Chnical improvement may be delayed for several months. 

TOXICITY AND MONITORING The toxic effects of antimalarial agents are described in Chapter 39. The incidence of retinopathy from chloroquine and hydroxychloroquine is low, as long as the doses are as described above and the medication is used for less than 10 years in patients with normal renal function. 

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