Hydroxychloroquine

Edina Avdic, Pharm.D.
Pediatric Dosing Author: Bethany Sharpless Chalk, Pharm.D., BCPPS

INDICATIONS

FDA

  • Indicated for the suppressive treatment and treatment of acute attacks of malaria due to Plasmodium vivax, P. malariae, P. ovale, and susceptible strains of P. falciparum
    • NOTE: not effective against chloroquine-resistant strains of P. falciparum
  • Treatment of discoid and systemic lupus erythematosus, and rheumatoid arthritis

NON-FDA APPROVED USES

FORMS

brand name

preparation

manufacturer

route

form

dosage^

cost*

Plaquenil

Hydroxychloroquine sulfate

Multiple manufacturers

PO

tablet

200 mg

$1.83-12.54

*Prices represent cost per unit specified, are representative of "Average Wholesale Price" (AWP).
^Dosage is indicated in mg unless otherwise noted.

USUAL ADULT DOSING

200 mg of hydroxychloroquine sulfate = 155 mg base

  • Malaria:
    • Treatment: 800 mg (=620 mg base) at time 0, followed by 400 mg (=310 mg base) at 6 h, 24 h and 48 h in combination with primaquine,
    • Prophylaxis: 400 mg weekly, start 1-2 weeks before and 4 weeks after the return from the area,
  • Chronic Q-fever: 200 mg (=155 base) q8h in combination with doxycycline for at least 18 months for native heart valves and 24 months for patients with prosthetic valves
  • Whipple’s disease: 200 mg q8h in combination with doxycycline
  • COVID-19: 400 mg (=310 mg base) q12h for 2 doses, followed by 200 mg (=155 base) q12h for 5 days has been suggested by in vitro study (PBPK model) OR 200 mg q8h has been used in one small study without a loading dose[1].
  • Rheumatologic diseases
    • Lupus erythematosus: 400 mg once or twice daily for several weeks to months, depending on patient response. Maintenance therapy is usually 200-400 mg daily to minimize toxicity.
    • Rheumatoid arthritis: 400 to 600 mg daily. After 5-10 days increase the dose gradually to the optimum response level. When a good response is obtained, the dosage should be reduced to 200 to 400 mg daily.

ADULT RENAL DOSING

DOSING IN HEMODIALYSIS

Usual dose

DOSING IN PERITONEAL DIALYSIS

Usual dose

DOSING IN RENAL REPLACEMENT THERAPY

No data

Other Adult Renal Dosing Information

Usual dosing. No renal adjustment is recommended by manufacturer, however use caution in patients with renal impairment. Close monitoring for adverse events (e.g. retinal toxicity) with long-term use and high doses is recommend.

PEDIATRIC DOSING

USUAL PEDIATRIC DOSING

200 mg of hydroxychloroquine sulfate = 155 mg base; all doses below are expressed as hydroxychloroquine sulfate

  • Malaria:
    • Treatment (Infants, children and adolescents): 13 mg/kg at time 0 (maximum initial dose = 800 mg), followed by 6.5 mg/kg at 6 h, 24 h, and 48 h after initial dose (maximum subsequent dose = 400 mg)
    • Prophylaxis (infants, children and adolescents): 6.5 mg/kg weekly (maximum dose = 400 mg), start 1-2 weeks before exposure and continue for at least 4 weeks after leaving an endemic area.
  • COVID-19: no published pediatric data available; proposed dosing based upon pharmacokinetic modeling
    • Treatment (children and adolescents): 6.5 mg/kg q12h on day 1 (maximum initial dose = 400 mg q12h), followed by 3.25 mg/kg q12h on days 2 - 5 (maximum dose = 200 mg q12h)
    • If tolerated, consider condensing maintenance dose to once daily in hospitalized patients (ex. 6.5 mg/kg q24h instead of 3.25 mg/kg q12h).
  • Juvenile rheumatoid arthritis (JRA) or systemic lupus erythematosus (SLE): 3 - 5 mg/kg/day divided in to 1 - 2 doses (maximum 400 mg/day, not to exceed 7 mg/kg/day).

PEDIATRIC RENAL DOSING

No renal adjustment is recommended by the manufacturer, however, use caution in patients with renal impairment. Close monitoring for adverse effects (ex. retinal toxicity) with long-term use and high doses is recommended.

OTHER PEDIATRIC INFORMATION

Administer with food or milk. Do not crush or divide film-coated tablets.

ADVERSE DRUG REACTIONS

GENERAL

  • Long-term hydroxychloroquine is contraindicated for patients with preexisting retinopathy of the eye or known hypersensitivity to 4-aminoquinoline compound, and children < 6 years of age.
    • Short-term use (e.g., 5-10 days) is safe even in patients with preexisting retinal disease.
  • Use of hydroxychloroquine in patients with psoriasis may precipitate a severe attack of psoriasis.

COMMON

  • Headache
  • Gastrointestinal complaints (diarrhea, anorexia, nausea, abdominal cramps and, on rare occasions, vomiting)
  • Blurring of vision due to a disturbance of accommodation; reversible and dose-dependent
  • Skin rash, pruritus

OCCASIONAL

  • Dizziness
  • Abnormal liver function tests
  • Sensory-motor disorders
  • Nervousness
  • Hydroxychloroquine can prolong the PR, QRS and QTc intervals, especially in patients with underlying risk factors or use in combination with other QT-prolonging drugs.
    • In one systemic review of cardiac toxicity (n=127) conduction disorders were the most common.
    • The median duration of treatment of 7 years (min 3 days –max of 35 years)[4].

RARE

  • Cardiomyopathy has been rarely reported with high daily dosages of hydroxychloroquine
  • Severe hypoglycemia
  • Bone marrow suppression
  • Fulminant hepatic failure
  • Extrapyramidal reactions
  • Suicidal behavior
  • Retinal toxicity is generally dose-related and NOT reversible.
    • Retinal damages usually occur with daily doses >5 mg/kg base of actual body weight, impaired renal function, elderly patients, duration of treatment >5 years, and concurrent treatment with tamoxifen citrate[6].
  • Pigmentary changes in skin and mucous membranes, bleaching of hair, and alopecia
  • Hemolytic anemia in patients with G6PD deficiency- the manufacturer recommends using caution.
    • However, one retrospective review no hemolysis was reported in patients who were G6PD deficient and were on hydroxychloroquine long term[5].

DRUG INTERACTIONS

Chloroquine (same can be assumed for hydroxychloroquine) is a substrate of CYP2C8 and CYP3A4, and to lesser extent CYP2D6, therefore co-administration with moderate and strong CYP2C8 and CYP3A4 inhibitors may result in increased plasma concentrations of hydroxychloroquine.

Drug-to-Drug Interactions

Drug

Effect of Interaction

Recommendations/Comments

Antacids

Antacids may reduce the absorption of hydroxychloroquine

Separate co-administration by 4-hour interval

Antidiabetic drugs and insulin

Hydroxychloroquine may enhance the effects of a hypoglycemic treatment

Reduction in doses of antidiabetic agents may be needed

Antiepileptic drugs

The activity of antiepileptic drugs might be impaired if co-administered with hydroxychloroquine

Monitor for seizures if coadministration can not be avoided

Cimetidine

Cimetidine can inhibit the metabolism of chloroquine and increase serum concentrations, which would also be expected for hydroxychloroquine.

Avoid combination if possible or monitor for toxicity if the combination can not be avoided

Cyclosporin

An increased plasma cyclosporine level was reported with co-administration with hydroxychloroquine

Monitor cyclosporin serum levels in patients receiving
concomitant treatment

Digoxin

Hydroxychloroquine may increase digoxin serum levels

Monitor digoxin serum levels in patients receiving
concomitant treatment

Mefloquine

Co-administration of hydroxychloroquine with other antimalarials that are known to lower the convulsion threshold (e.g. mefloquine) may increase the risk of convulsions

Avoid co-administration if possible or monitor for seizures if coadministration can not be avoided

Praziquantel

Chloroquine has been reported to reduce the bioavailability of praziquantel, which would also be expected for hydroxychloroquine

Avoid coadministration

Rabies vaccine

Chloroquine may decrease rabies-neutralizing antibody titer with co-administration, same would be expected with hydroxychloroquine[12]

Avoid coadministration

SPECTRUM

P. ovale, P. malariae, and chloroquine-sensitive P. falciparum and P. vivax; Tropheryma whipplei, Coxiella burnetii, and more recently SARS-CoV-2. It has modest activity in vitro against HIV alone and synergistic with select antivirals.

RESISTANCE

Hydroxychloroquine is not effective against chloroquine-resistant strains of P. falciparum and is not active against the exo-erythrocytic forms of P. vivax, P. ovale and P. malarias.

PHARMACOLOGY

MECHANISM

  • Hydroxychloroquine belongs to a 4-aminoquinoline antibacterial class. Like chloroquine, it is a weak base and may exert its effect by concentrating the acid vesicles of the parasite and by inhibiting polymerization of heme, although the exact mechanism against Plasmodium is unknown.
  • It accumulates in lymphocytes and macrophages resulting in anti-inflammatory properties, which is the main reason for its use in rheumatoid arthritis and lupus erythematosus diseases[10].
  • Chloroquine increases endosomal pH required for virus/cell fusion, as well as interfering with the glycosylation of cellular receptors of SARS-CoV.
    • Against COVID-19, chloroquine functioned at both entry and at postentry stages of infection in Vero E6 cells.
    • Hydroxychloroquine similar to chloroquine decreases the pH and confers antiviral effects against SARS-CoV-2.
    • Furthermore, hydroxychloroquine has an immunomodulating effect, it reducesT-cell activation, differentiation and expression of co-stimulatory proteins and cytokines produced by T cells and B cells (e.g. IL-1, IL-6)[2].

PHARMACOKINETIC PARAMETERS

Absorption

Hydroxychloroquine is almost completely and rapidly absorbed after oral administration. The mean fraction of the dose absorbed was 0.74. Peak plasma levels are reached 3-4 hours.

Metabolism and Excretion

  • Urine excretion of the unchanged drug was ~16-30% and does not correlate with creatinine clearance.
  • Urine levels remained detectable after 3 months.
  • Hydroxychloroquine is metabolized in the liver into 3 oxidative metabolites: bidesethyhydroxylchloroquine, desethylhydroxychloroquine, and desethylchloroquine.

Protein Binding

~50%

Cmax, Cmin, and AUC

  • Peak blood concentrations were ranged from 1161 ng/ml to 2436 ng/ml after intravenous administration of 155 mg and 6 months following 310 mg infusion.
  • The efficacy of hydroxychloroquine is found to be concentration-dependent[3][11].

T1/2

Terminal half-life= 40-50 days

Distribution

Extensive tissue uptake and a large volume of distribution. The highest tissue distribution is in the choroid and ciliary body of the eye.

Hydroxychloroquine lung concentrations are significantly higher than the blood concentrations[3].

DOSING FOR DECREASED HEPATIC FUNCTION

  • Use with caution in patients with hepatic impairment. No dosing adjustment is recommended by the manufacturer, but a reduction in dosage may be necessary

PREGNANCY RISK

  • The use of hydroxychloroquine in pregnancy without an increase in the rate of birth defects has been reported in the literature. It is generally recommended for pregnant patients with an autoimmune disease.
  • Embryonic deaths and ocular malformations in the offspring have been reported when pregnant rats received large doses of chloroquine.

BREAST FEEDING COMPATIBILITY

Hydroxychloroquine is excreted in human milk (~2%), and infants are extremely sensitive to the toxic effects of 4-aminoquinolines. Limited data are available on the safety of breastfed infants during hydroxychloroquine long-term treatment. Risk vs. benefits should be considered when deciding to initiate hydroxychloroquine to a nursing mother.

COMMENTS

  • Hydroxychloroquine is a hydroxy-analog of chloroquine that is better tolerated. Initially developed for malaria treatment, but over the years has shown to have immunomodulatory properties and has been used for the treatment of autoimmune diseases such as treatment of rheumatoid arthritis and lupus.
  • Decades of use in chronic inflammatory conditions and malaria prophylaxis suggest that it is a relatively safe drug with a low incidence of adverse events.
  • Retinopathy is one of the most serious adverse events associated with hydroxychloroquine and it is NOT reversible. The American Academy of Ophthalmology recommends screening for hydroxychloroquine-related retinopathy: examination prior to therapy initiation to rule out preexisting maculopathy and annual screening after 5 years for patients on acceptable doses and without major risk factors[6].

Malaria:

  • Hydroxychloroquine is recommended in combination with primaquine for the treatment of uncomplicated malaria caused by chloroquine-sensitive P. falciparum or P. vivax, and P. malariae, P. knowlesi, P. ovale from all regions. It is also one of the agents that can be used for malaria prophylaxis in select regions.

COVID-19 (SARS-CoV-2)

  • On March 28th, 2020. FDA issued Emergency Use Authorization for use of chloroquine phosphate or hydroxychloroquine sulfate supplied from the Strategic National Stockpile (SNS) for treatment of COVID-19. According to FDA, “hydroxychloroquine sulfate may only be used to treat adult and adolescent patients who weigh 50 kg or more and are hospitalized with COVID-19, for whom a clinical trial is not available, or participation is not feasible”.
  • Hydroxychloroquine has been used in a recent COVID-19 outbreak. Limited available data are largely based on in vitro studies and clinical series and one small RCT showing no effect.
    • In vitro activity against COVID-19 (SARS-CoV-2), more potent than chloroquine[3].
    • In a small, observational, non-randomized study of (n=36) patients with SARS-CoV-2 infection, administration of hydroxychloroquine 200 mg q8h for 10 days (n=20) resulted in higher clearance of virus (70%) on day 6 compared to controls (12.5%). Six patients also received azithromycin, and authors argued in a post-hoc analysis that addition of azithromycin resulted in even higher, but statistically nonsignificant clearance[1]. This study, however, has many limitations including small sample size, exclusions from analysis of patients who were lost to follow-up (e.g. escalation of care, death), no clinical outcomes were reported or colation of viral clearance and clinical outcomes has been made.
    • A pilot RCT of 30 patients comparing HCQ v. placebo found that on day 7, COVID-19 nucleic acid of throat swabs was negative in 13 (86.7%) cases in the HCQ group and 14 (93.3%) cases in the control group (P>0.05). There was no significant clinical difference between the groups. The study suggests that if HCQ has an effect it is at most modest, so larger studies need to be performed.
    • Larger and properly designed studies are needed to determine the benefits of hydroxychloroquine in the treatment of COVID-19-positive patients and the role of combination therapy (e.g. with azithromycin).
  • Hydroxychloroquine is currently being investigated in post-exposure prophylaxis in healthcare workers (NCT04308668).

Basis for recommendation

  1. Gautret P, Lagier JC, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020.  [PMID:32205204]

    Comment: In this observational, non-randomized very small study (n=36) patients with SARS-CoV2 infection (6 patients were asymptomatic, 22 had URTI, 8 had LRTI) who received hydroxychloroquine 200 mg q8h for 10 days (n=20) were compared to controls (n=16, patients who did not receive hydroxychloroquine). On day 6, 70% of patients in hydroxychloroquine group clearance of virus compared to 12.5% in control group (p=0.001). Study excluded form analysis patients who were lost to follow up (e.g. escalation of care, death, incomplete treatment). No clinical outcomes were reported. Six patients in this study also received azithromycin along with hydroxychloroquine. Authors concluded that combination therapy was more effective in clearing virus, however this was not statistically significant and groups were not well balanced at baseline (e.g. more patients in monotherapy had lower CT values).

References

  1. Zhou D, Dai SM, Tong Q. COVID-19: a recommendation to examine the effect of hydroxychloroquine in preventing infection and progression. J Antimicrob Chemother. 2020.  [PMID:32196083]

    Comment: A brief review paper proving in great detail mechanism of action of chloroquine/hydroxychloroquine against SARS-CoV-2 virus and safety of both agents.

  2. Yao X, Ye F, Zhang M, et al. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Clin Infect Dis. 2020.  [PMID:32150618]

    Comment: In vitro study (PBPK model) suggesting that hydroxychloroquine is more potent than chloroquine in decreasing viral replication. EC50 values for chloroquine were >100 and 18.01 mcg at 24 and 48 hours, while EC50 values for hydroxychloroquine were 6.25 and 5.85 mcg at 24 and 48 hours. The inhibitory chloroquine was poor, the inhibition did not exceed 50%. The Efficacy was found to be concentration-dependent. Hydroxychloroquine was also found to have higher lung concentrations on days 1, 3, 5, and 10 compared to chloroquine.
    Rating: Important

  3. Chatre C, Roubille F, Vernhet H, et al. Cardiac Complications Attributed to Chloroquine and Hydroxychloroquine: A Systematic Review of the Literature. Drug Saf. 2018;41(10):919-931.  [PMID:29858838]

    Comment: A systematic review (n=127 patients) investigated cardiac complications attributed to chloroquine and hydroxychloroquine. 58.3% of patients received chloroquine and 39.4% received hydroxychloroquine with a median duration of treatment of 7 years (min 3 days –max of 35 years). Conduction disorders were the most common, followed by heart failure, ventricular hypertrophy, hypokinesia, heart failure, pulmonary arterial hypertension and valvular dysfunction. For 78 patients reported to have been withdrawn from treatment, 44.9% recovered normal heart function, 12.9% had irreversible damage and 30.8% death.
    Rating: Important

  4. Mohammad S, Clowse MEB, Eudy AM, et al. Examination of Hydroxychloroquine Use and Hemolytic Anemia in G6PDH-Deficient Patients. Arthritis Care Res (Hoboken). 2018;70(3):481-485.  [PMID:28556555]

    Comment: A retrospective review of 275 patients who had G6PD levels measured and were on hydroxychloroquine, only 11 patients (4%) were G6PD deficient (all African American). Two patients developed hemolysis that occurred while they were not taking hydroxychloroquine. No hemolysis was reported in more than 700 months of hydroxychloroquine exposures among 11 patients who were G6PD deficient.
    Rating: Important

  5. Marmor MF, Kellner U, Lai TY, et al. Recommendations on Screening for Chloroquine and Hydroxychloroquine Retinopathy (2016 Revision). Ophthalmology. 2016;123(6):1386-94.  [PMID:26992838]

    Comment: 2016 American Academy of Ophthalmology recommendations on screening for chloroquine and hydroxychloroquine-related retinopathy: examination prior to therapy initiation to rule out preexisting maculopathy and annual screening after 5 years for patients on acceptable doses and without major risk factors

  6. Lagier JC, Fenollar F, Lepidi H, et al. Treatment of classic Whipple's disease: from in vitro results to clinical outcome. J Antimicrob Chemother. 2014;69(1):219-27.  [PMID:23946319]

    Comment: Very small retrospective case series of 29 patients diagnosed with Whipple’s disease. 15 patients were initially treated with hydroxychloroquine 200 mg q8h and doxycycline 100 mg q12h (+sulfadiazine or trimethoprim/sulfamethoxazole in 5 patients with neurologic findings). This treatment combination was associated with a better outcome (0/13 failures) compared to 14 patients who were first treated initially with trimethoprim/sulfamethoxazole.

  7. Kersh GJ. Antimicrobial therapies for Q fever. Expert Rev Anti Infect Ther. 2013;11(11):1207-14.  [PMID:24073941]

    Comment: Review paper on Q-fever therapies hydroxychloroquine 200 mg q8h in combination with doxycycline is commonly used for chronic Q-fever disease for 18-24 months.

  8. Lim HS, Im JS, Cho JY, et al. Pharmacokinetics of hydroxychloroquine and its clinical implications in chemoprophylaxis against malaria caused by Plasmodium vivax. Antimicrob Agents Chemother. 2009;53(4):1468-75.  [PMID:19188392]

    Comment: PK study of hydroxychloroquine and its metabolites conducted in healthy subjects and patients receiving hydroxychloroquine 400 mg weekly for prophylaxis for P. vivax in South Korea. Plasma concentrations were analyzed by noncompartmental and mixed-effect modeling. 2-compartment model and first-order absorption best described data. Clearance was 15.5 L, central and peripheral Vd were 733 L and 1630 L respectively. The average steady-state concentrations were 0.17 mcg/ml was predicted in the model.

  9. Savarino A, Boelaert JR, Cassone A, et al. Effects of chloroquine on viral infections: an old drug against today's diseases? Lancet Infect Dis. 2003;3(11):722-7.  [PMID:14592603]

    Comment: The article discusses the mechanism and activity of chloroquine/hydroxychloroquine against viral infections such as HIV and SARS. Its immunomodulatory effects are also reviewed in detail: chloroquine/hydroxychloroquine suppresses the production/release of tumor necrosis factor and IL-6, which mediate the inflammatory complications of several viral diseases.

  10. Munster T, Gibbs JP, Shen D, et al. Hydroxychloroquine concentration-response relationships in patients with rheumatoid arthritis. Arthritis Rheum. 2002;46(6):1460-9.  [PMID:12115175]

    Comment: Study in RA patients evaluating dose-response relationship and dose-toxicity relationship. A randomized, double-blind, parallel trial evaluating 400 mg, 800 mg, 1200 mg daily for 6 weeks followed by maintenance of 400 mg daily. Blood concentrations were obtained from 123 patients for analysis of hydroxychloroquine and its 3 metabolites (bides-ethyl chloroquine, desethylhydroxychloroquine, desethylchloroquine). There was a positive relationship between Paulus 20% improvement criteria response and blood concentrations at week 6: 48% in patients receiving 400 mg daily, 58% in 800 mg daily and 64% in 1200 mg daily. Ocular adverse events were observed in patients with higher bides-ethyl chloroquine levels. No clinical loss of vision was noted.

  11. Pappaioanou M, Fishbein DB, Dreesen DW, et al. Antibody response to preexposure human diploid-cell rabies vaccine given concurrently with chloroquine. N Engl J Med. 1986;314(5):280-4.  [PMID:3510393]

    Comment: This randomized trial demonstrates that co-administration of weekly chloroquine beginning 9 days before the first dose of rabies vaccine administration was negatively associated with log antibody titers.

  12. CDC Guidelines for the treatment of malaria: [https://www.cdc.gov…]

    Comment: Hydroxychloroquine is recommended in combination with primaquine for the treatment of uncomplicated malaria caused by chloroquine-sensitive P. falciparum or P. vivax, and P. malariae, P. knowlesi, P. ovale from all regions.
    Rating: Important

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Last updated: April 8, 2020