Hydroxychloroquine, a 4-aminoquinoline derivative, is an antimalarial agent.100
Hydroxychloroquine is used for the prevention or chemoprophylaxis of malaria caused by Plasmodium malariae , P. ovale , chloroquine-susceptible P. vivax , or chloroquine-susceptible P. falciparum 100, 115, 121 and for the treatment of uncomplicated malaria caused by P. malariae , P. knowlesi , P. ovale , chloroquine-susceptible P. vivax , or chloroquine-susceptible P. falciparum in adults and children.100, 143, 144
Chloroquine has historically been considered the drug of choice for prevention of malaria in travelers to areas where chloroquine-resistant malaria has not been reported121, 134 and for treatment of malaria acquired in areas where chloroquine-resistant malaria has not been reported.143, 144 Hydroxychloroquine may be used when chloroquine is unavailable115, 121, 134, 143, 144 and may be better tolerated than chloroquine.115 However, chloroquine-resistant Plasmodium also are resistant to hydroxychloroquine.100
The fact that chloroquine-resistant P. falciparum has now been confirmed in all areas with P. falciparum malaria, except the Caribbean and Central America west of the Panama Canal, should be considered when selecting an antimalarial for prevention or treatment of malaria.115, 121, 143 The fact that P. vivax with resistance or decreased susceptibility to chloroquine has been confirmed in Papua New Guinea and Indonesia also should be considered.121, 143 Chloroquine (or hydroxychloroquine) should only be used for the prevention or treatment of malaria in areas where chloroquine resistance has not been reported.115, 121, 143
Because hydroxychloroquine is active only against the asexual erythrocytic forms of Plasmodium (not exoerythrocytic stages), the drug cannot prevent delayed primary attacks or relapse of P. ovale or P. vivax malaria and cannot provide a radical cure in malaria caused by these species.100, 115 Therefore, an 8-aminoquinoline antimalarial (14-day regimen of primaquine phosphate or single dose of tafenoquine) is indicated in addition to hydroxychloroquine prophylaxis if travelers were exposed in areas with P. ovale or P. vivax malaria and also is indicated in conjunction with hydroxychloroquine to eradicate hypnozoites and prevent relapse in patients being treated for P. ovale or P. vivax malaria.100, 115, 143, 144
The most appropriate regimen for the treatment of malaria is selected based on the infecting species of Plasmodium , malaria severity and clinical status of the patient, expected drug susceptibility as determined by the geographic area where malaria was acquired, and prior receipt of antimalarials (e.g., drugs used for malaria chemoprophylaxis).143 Although uncomplicated malaria can be treated with various oral antimalarial regimens, patients with severe malaria require aggressive treatment with a parenteral antimalarial regimen as soon as possible after the diagnosis.143, 144 Hydroxychloroquine is used for the treatment of uncomplicated malaria, but is not recommended for the treatment of severe malaria.143, 144
Information on the risk of malaria transmission in specific countries, information on mosquito avoidance measures, recommendations regarding whether chemoprophylaxis of malaria is indicated, and information on the choice of antimalarials for prevention of malaria are available from the US Centers for Disease Control and Prevention (CDC) at [Web] and [Web].115
Information on recommended regimens for the treatment of malaria is available from CDC at [Web].143, 144 Assistance with diagnosis or treatment of malaria is available by contacting the CDC Malaria Hotline at 770-488-7788 or 855-856-4713 from 9:00 a.m. to 5:00 p.m. Eastern Standard Time or the CDC Emergency Operation Center at 770-488-7100 after hours and on weekends and holidays143, 144
Hydroxychloroquine is used for the treatment of systemic lupus erythematosus and chronic discoid lupus erythematosus in adults.100 If hydroxychloroquine is used for prolonged periods in the treatment of lupus erythematosus, the increased risk of serious adverse effects (e.g., retinopathy) should be considered.100, 213
Hydroxychloroquine is used in the treatment of acute and chronic rheumatoid arthritis in adults.100, 103 Hydroxychloroquine is one of several conventional disease-modifying antirheumatic drugs (DMARDs) that can be used when conventional DMARD therapy is appropriate.103 If hydroxychloroquine is used for prolonged periods in the treatment of rheumatoid arthritis, the increased risk of serious adverse effects (e.g., retinopathy) should be considered.100
The most recent guidelines available from the American College of Rheumatology (ACR) should be consulted for information on use of hydroxychloroquine in the treatment of rheumatoid arthritis.103
Although doxycycline usually is the drug of choice for the treatment of acute Q fever caused by Coxiella burnetii ,113, 115 a regimen of doxycycline and hydroxychloroquine is recommended by CDC and others for the treatment of chronic Q fever† involving endocarditis, vascular infection, or non-cardiac organ disease.111, 112, 113, 122
In a limited study in patients with confirmed C. burnetii infection and chronic endocarditis, a regimen of doxycycline and hydroxychloroquine was associated with a lower relapse rate than a regimen of doxycycline and ofloxacin.111 Although both regimens require long-term therapy, the mean duration of therapy for cured patients was 55 months for those who received the doxycycline and quinolone regimen compared with 31 months for those who received the doxycycline and hydroxychloroquine regimen.111 Prolonged therapy (at least 18 months) with the doxycycline and hydroxychloroquine regimen is necessary to prevent relapse.111
Hydroxychloroquine has been used in the treatment of porphyria cutanea tarda†.114, 116, 117, 123
Coronavirus Disease 2019 (COVID-19)
Hydroxychloroquine and chloroquine were targeted for investigation as potential options for the treatment and prevention of coronavirus disease 2019 (COVID-19)† caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during the early stages of the COVID-19 pandemic based on some evidence of in vitro activity against SARS-CoV-2,198, 212, 231 the possibility that the immunomodulatory activity of the drugs might contribute to anti-inflammatory responses in patients with viral infections,193, 198, 213, 215, 216, 231 and initial anecdotal reports and preliminary information from small trials.197, 218 However, safety and efficacy of hydroxychloroquine and chloroquine for the treatment or prevention of COVID-19 have not been established,230 and the National Institutes of Health (NIH)231 and Infectious Diseases Society of America (IDSA)232 recommend against use of the drugs (alone or in conjunction with other antivirals or other drugs) in the treatment or prevention of COVID-19.
During the early stages of the COVID-19 pandemic, FDA made hydroxychloroquine and chloroquine available is the US for a few months (March 28, 2020 to June 15, 2020) under an FDA emergency use authorization (EUA) to facilitate availability of the drugs for treatment of COVID-19,224 and various clinical trials were initiated in the US and other countries to evaluate use of the drugs (alone or in conjunction with other antivirals or other drugs) for the treatment or prevention of COVID-19.194, 200, 221 FDA revoked the EUA for hydroxychloroquine and chloroquine on June 15, 2020 after concluding that, based on the totality of scientific evidence that became available after the EUAs was issued, it is unlikely that the drugs may be effective in treating COVID-19 and, in light of reports of serious cardiac adverse events and several reported cases of methemoglobinemia in COVID-19 patients, the known and potential benefits of hydroxychloroquine and chloroquine do not outweigh the known and potential risks for the use authorized in the EUA.230 FDA also stated that the suggested hydroxychloroquine and chloroquine dosage regimens are unlikely to produce an antiviral effect; earlier observations of decreased viral shedding with hydroxychloroquine or chloroquine treatment were not consistently replicated; and data from a large randomized controlled trial showed no difference between hydroxychloroquine and standard of care alone.230
Hydroxychloroquine sulfate is administered orally.100 The drug should be administered with food or milk.100
The film-coated tablets of hydroxychloroquine should not be crushed or divided.100
Dosage of hydroxychloroquine sulfate is expressed in terms of hydroxychloroquine sulfate or in terms of the base (hydroxychloroquine).100
Each 200-mg tablet of hydroxychloroquine sulfate contains 155 mg of the base.100
Prevention of Malaria in Areas Without Chloroquine-resistant Plasmodium
If hydroxychloroquine is used for prevention of malaria in travelers to areas where chloroquine-resistant Plasmodium has not been reported, hydroxychloroquine prophylaxis should be initiated 1-2 weeks prior to entering the malarious area and continued during the stay and for 4 weeks after leaving the area.100, 115, 121 Hydroxychloroquine prophylaxis is given once weekly and should be administered on the same day each week.100, 115
For prevention of malaria, the usual adult dosage is 400 mg of hydroxychloroquine sulfate (310 mg of the base) once weekly, and the usual pediatric dosage is 6.5 mg/kg of hydroxychloroquine sulfate (5 mg/kg of the base) once weekly.100, 115 Pediatric dosage should not exceed 400 mg of hydroxychloroquine sulfate (310 mg of the base) once weekly regardless of weight.100, 115 The manufacturer states that the tablets are not recommended in pediatric patients weighing less than 31 kg.100
Because hydroxychloroquine cannot prevent delayed primary attacks or relapse of P. ovale or P. vivax malaria and cannot provide a radical cure in malaria caused by these species, an 8-aminoquinoline antimalarial (14-day regimen of primaquine phosphate or single dose of tafenoquine) also is indicated if exposure to malaria occurred in areas with P. ovale or P. vivax malaria.115
Treatment of Uncomplicated Chloroquine-susceptible Malaria
For the treatment of uncomplicated malaria caused by P. malariae , P. knowlesi , P. ovale , chloroquine-susceptible P. vivax , or chloroquine-susceptible P. falciparum , adults should receive an initial dose of 800 mg of hydroxychloroquine sulfate (620 mg of the base) followed by 400 mg of hydroxychloroquine sulfate (310 mg of the base) given at 6, 24, and 48 hours after the initial dose.100, 144
For the treatment of uncomplicated malaria caused by P. malariae , P. knowlesi , P. ovale , chloroquine-susceptible P. vivax , or chloroquine-susceptible P. falciparum in pediatric patients, an initial dose of 13 mg/kg of hydroxychloroquine sulfate (10 mg/kg of the base) should be given followed by 6.5 mg/kg of hydroxychloroquine sulfate (5 mg/kg of the base) given at 6, 24, and 48 hours after the initial dose.100, 144 Pediatric dosage for the initial dose should not exceed 800 mg of hydroxychloroquine sulfate and pediatric dosage for each of the 3 subsequent doses should not exceed 400 mg of hydroxychloroquine sulfate.100 The manufacturer states that the tablets are not recommended in pediatric patients weighing less than 31 kg.100
Because hydroxychloroquine cannot prevent relapse of P. ovale or P. vivax malaria, an 8-aminoquinoline antimalarial (14-day regimen of primaquine phosphate or single dose of tafenoquine) also is indicated to provide a radical cure whenever hydroxychloroquine is used for the treatment of malaria caused by these species.143, 144
For the treatment of systemic lupus erythematosus or chronic discoid lupus erythematosus in adults, the manufacturer recommends a dosage of 200 mg of hydroxychloroquine sulfate once daily or 400 mg of hydroxychloroquine sulfate daily given as a single dose or in 2 divided doses.100
For the treatment of rheumatoid arthritis in adults, the manufacturer recommends an initial dosage of 400-600 mg of hydroxychloroquine sulfate daily given as a single dose or in 2 divided doses.100 For chronic maintenance therapy, the manufacturer recommends a dosage of 200 mg of hydroxychloroquine sulfate once daily or 400 mg of hydroxychloroquine sulfate daily given as a single dose or in 2 divided doses.100 Daily dosage exceeding 5 mg/kg of hydroxychloroquine sulfate increases the risk of retinopathy (see Cautions).100
The therapeutic effects of hydroxychloroquine in adults with rheumatoid arthritis are cumulative and maximum effects may require weeks to months of treatment with the drug.100
For the treatment of chronic Q fever† in adults with endocarditis, vascular infection, or non-cardiac organ disease, CDC recommends 200 mg of hydroxychloroquine sulfate every 8 hours in conjunction with doxycycline (100 mg every 12 hours).122 The duration of treatment is based on serologic response and evidence of clinical improvement.122 The regimen should be continued for at least 18 months in those with endocarditis.122
Dosage in Renal and Hepatic Impairment
Hydroxychloroquine dosage may need to be reduced in patients with renal or hepatic impairment;100 the manufacturer makes no specific recommendations for such individuals.100
In dosages used for prevention and treatment of malaria, adverse effects of 4-aminoquinoline derivatives (chloroquine and hydroxychloroquine) are usually mild and reversible. However, prolonged therapy or high dosage of the drugs, as used in the treatment of rheumatoid arthritis or lupus erythematosus, has been associated with serious and sometimes irreversible toxicity including retinopathy. Although adverse reactions reported with hydroxychloroquine are similar to those reported for chloroquine, prolonged therapy with high dosages of hydroxychloroquine has been reported to be associated with fewer adverse effects than prolonged use of equivalent dosages of chloroquine.
Life-threatening and fatal cardiotoxicity, including cardiomyopathy, has been reported in patients receiving hydroxychloroquine;100 signs and symptoms of cardiac compromise have been reported with both acute and chronic treatment with the drug.100 Patients may present with ventricular hypertrophy, pulmonary hypertension, and conduction disorders including sick sinus syndrome; ECG findings include atrioventricular, right or left bundle branch block.100
Hydroxychloroquine potentially may prolong the QT interval.100 Ventricular arrhythmias (including torsades de pointes) have been reported in patients receiving the drug.100 Because the magnitude of QT prolongation may increase with increasing concentrations of the drug, the recommended dosage should not be exceeded.100 Use of hydroxychloroquine should be avoided in patients with congenital or documented acquired QT prolongation and/or known risk factors for prolongation of the QT interval such as cardiac disease (e.g., heart failure, myocardial infarction), proarrhythmic conditions (e.g., bradycardia [less than 50 bpm]), history of ventricular dysrhythmias, uncorrected hypokalemia and/or hypomagnesemia, and concomitant use of drugs known to prolong the QT interval.100
Cardiac function should be monitored as clinically indicated in patients receiving hydroxychloroquine and concomitant use with other drugs with potential to prolong the QT interval should be avoided.100 If cardiotoxicity is suspected, the drug should be discontinued.100
Irreversible retinal damage has occurred in some patients treated with hydroxychloroquine and is related to cumulative dosage and treatment duration.100
Risk factors for retinal damage associated with hydroxychloroquine include daily dosage of 5 mg/kg or more of hydroxychloroquine sulfate, treatment duration greater than 5 years, renal impairment, concomitant use of other drugs with adverse ocular effects (e.g., tamoxifen), and concurrent macular disease.100
In patients receiving long-term treatment with hydroxychloroquine, a baseline ocular examination is recommended within the first year of treatment and should include best corrected distance visual acuity (BCVA), an automated threshold visual field (VF) of the central 10 degrees (with retesting if an abnormality is noted), and spectral domain ocular coherence tomography (SD-OCT).100 For patients at higher risk of retinal damage, monitoring should include annual examinations that include BCVA, VF, and SD-OCT.100 For patients without significant risk factors, annual retinal exams can usually be deferred until 5 years of treatment.100 In patients of Asian descent, retinal toxicity may first be noticed outside the macula; therefore, visual field testing should be performed in the central 24 degrees (instead of the central 10 degrees).100
If ocular toxicity is suspected, hydroxychloroquine should be discontinued and the patient monitored closely because retinal changes and visual disturbances may progress even after the drug is discontinued.100
Dermatologic and Sensitivity Reactions
Serious adverse dermatologic reactions have been reported in patients receiving hydroxychloroquine, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP).100
Patients should be monitored for serious skin reactions, especially those receiving other drugs associated with dermatitis.100 Hydroxychloroquine should be discontinued if a severe dermatologic reaction occurs.100
Worsening of Psoriasis and Porphyria
Use of hydroxychloroquine in patients with psoriasis may precipitate a severe psoriasis flare-up.100 Hydroxychloroquine should be avoided in patients with psoriasis, unless benefits to the patient outweigh possible risks.100
Use of hydroxychloroquine in patients with porphyria may exacerbate porphyria.100 Hydroxychloroquine should be avoided in patients with porphyria, unless benefits to the patient outweigh possible risks.100
The most common adverse reactions reported with hydroxychloroquine are nausea, vomiting, diarrhea, and abdominal pain.100
Hydroxychloroquine may cause myelosuppression, including aplastic anemia, agranulocytosis, leukopenia, or thrombocytopenia.100 Complete blood cell counts (CBCs) should be monitored periodically in patients receiving prolonged hydroxychloroquine therapy.100 If myelosuppression develops and cannot be attributable to the disease being treated, hydroxychloroquine should be discontinued.100
Hemolysis has been reported in patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency.100 Patients should be monitored for hemolytic anemia, especially those receiving other drugs associated with hemolysis.100
Skeletal muscle myopathy or neuropathy leading to progressive weakness and atrophy of proximal muscle groups, depressed tendon reflexes, and abnormal nerve conduction, have been reported in patients receiving hydroxychloroquine.100 Muscle and nerve biopsies have demonstrated bodies and muscle fiber atrophy with vacuolar changes.100
Muscle strength and deep tendon reflexes should be assessed periodically in patients receiving long-term hydroxychloroquine therapy.100 If muscular weakness occurs, the drug should be discontinued.100
Suicidal behavior has been reported in patients receiving hydroxychloroquine.100 Patients should be advised to contact their healthcare provider if they experience new or worsening depression, suicidal thoughts or behavior, or mood changes.100 The risks and benefits of continued treatment with hydroxychloroquine should be assessed for patients who develop such symptoms.100
Severe and potentially life-threatening hypoglycemia has been reported in patients receiving hydroxychloroquine who were or were not receiving treatment with antidiabetic agents.100 Blood glucose should be assessed in patients presenting with clinical symptoms suggestive of hypoglycemia and antidiabetic treatment should be adjusted as necessary.100
Precautions and Contraindications
Hydroxychloroquine is contraindicated in patients who are hypersensitive to 4-aminoquinoline derivatives (hydroxychloroquine and chloroquine).100
CDC issued a health advisory concerning the inappropriate use of hydroxychloroquine and chloroquine, including inappropriate use of non-pharmaceutical preparations of the drugs.222 Clinicians should advise patients and the public to not ingest aquarium products or any other chemical products that contain chloroquine since these products are not intended for human consumption and can lead to serious health consequences, including death.222 Hydroxychloroquine and chloroquine should be used only under the supervision of a healthcare provider.222 Inappropriate uses of hydroxychloroquine and chloroquine include taking any commercially available non-pharmaceutical preparations of the drugs, taking the drugs without a prescription or without supervision by a healthcare provider, and taking additional doses of the drugs not recommended by a healthcare provider.222
Because life-threatening and fatal cardiotoxicity has been reported with hydroxychloroquine, cardiac function should be monitored as clinically indicated in patients receiving the drug and concomitant use with other drugs with potential to prolong the QT interval should be avoided.100 Electrolyte imbalances should be corrected prior to initiation of hydroxychloroquine.100 Patients should be informed that serious cardiac effects, including life-threatening and fatal cases, have been reported with use of hydroxychloroquine and advised to seek medical attention immediately if they experience any symptoms of heart rhythm changes, including fast or irregular heartbeat, lightheadedness, dizziness, or syncope.100
Because retinopathy and maculopathy have been reported, ophthalmologic examinations should be performed periodically during therapy whenever long-term use of the drug is contemplated.100 Patients should be informed that irreversible retinal damage has been reported in some patients treated with hydroxychloroquine and advised of the importance of ophthalmology visits to monitor their eyes.100 Patients should be instructed to seek medical attention promptly if they experience decreased vision or decreased dark adaptation.100
Patients should be informed that severe, life-threatening skin reactions have been reported in some patients receiving hydroxychloroquine and advised to seek medical attention immediately if they experience blisters in the mouth or on the skin, eyes, or lips or experience itching or burning, with or without fever.100
CBCs should be performed periodically in patients receiving prolonged hydroxychloroquine therapy.100 Hydroxychloroquine should be discontinued if there is evidence of any severe blood disorder not attributable to the disease being treated.100
Patients should be informed that muscle weakness and atrophy have been reported with hydroxychloroquine and advised to report any symptoms of muscle weakness to their clinician.100
Because suicidal behavior has been reported, patients receiving the drug should be advised to seek immediate medical attention if they experience new or worsening depression, suicidal thoughts, or other mood changes.100
Because severe, potentially life-threatening hypoglycemia has been reported in patients receiving hydroxychloroquine (including those who were or were not receiving treatment with antidiabetic agents), patients should be warned about the risk of hypoglycemia and associated clinical signs and symptoms.100 Patients with diabetes mellitus should be advised to monitor blood sugar levels and seek medical attention if they develop any signs and symptoms of hypoglycemia (e.g., sweating, shakiness, weakness, dizziness, tachycardia, nausea, blurred vision, confusion, fainting, loss of consciousness).100
Hydroxychloroquine dosage may need to be reduced in individuals with impaired renal or hepatic function.100
Safety and efficacy of hydroxychloroquine have been established in pediatric patients for the treatment of uncomplicated malaria cause by P. malariae , P. ovale , P. vivax , or chloroquine-susceptible P. falciparum and for the prophylaxis of malaria in geographic areas where chloroquine resistance has not been reported.100 The manufacturer states that hydroxychloroquine film-coated tablets are not recommended in pediatric patients weighing less than 31 kg because the tablets cannot be crushed or divided.100
Safety and efficacy of hydroxychloroquine have not been established for the treatment of systemic lupus erythematosus or juvenile idiopathic arthritis in pediatric patients.100
Clinical trials of hydroxychloroquine did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger patients.100
Hydroxychloroquine is substantially eliminated by the kidneys, and the risk of toxic reactions to the drug may be greater in patients with impaired renal function.100 Because geriatric patients are more likely to have decreased renal, hepatic, or cardiac function and concomitant disease or other drug therapy, hydroxychloroquine dosage for such patients should be selected starting with the lowest recommended dosage.100
Mutagenicity and Carcinogenicity
The mutagenic potential of hydroxychloroquine has not been evaluated.100 However, chloroquine has been shown to be a catalytic inhibitor of DNA repair enzymes (topoisomerase II) and to produce weak genotoxic effects through this mode of action.100
Long-term studies in animals have not been conducted to evaluate the carcinogenic potential of hydroxychloroquine.100
The manufacturer states that decades of clinical experience with hydroxychloroquine and data available from published epidemiologic and clinical studies of the drug in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.100
There are risks to the mother and fetus associated with untreated or increased disease activity from malaria, rheumatoid arthritis, and systemic lupus erythematosus during pregnancy.100 Malaria during pregnancy increases the risk for adverse pregnancy outcomes, including maternal anemia, prematurity, spontaneous abortion, and stillbirth.100 Published data suggest that increased disease activity in pregnant women with rheumatoid arthritis is associated with a risk of adverse pregnancy outcomes, including preterm delivery (before 37 weeks of gestation), low birth weight infants (less than 2.5 kg), and small for gestational age at birth.100 Pregnant women with systemic lupus erythematosus, especially those with increased disease activity, are at increased risk of adverse pregnancy outcomes, including spontaneous abortion, fetal death, preeclampsia, preterm birth, and intrauterine growth restriction, and passage of maternal auto-antibodies across the placenta may result in neonatal illness, including neonatal lupus and congenital heart block.100
Hydroxychloroquine readily crosses the placenta with cord blood concentrations corresponding to maternal plasma concentrations.100 The manufacturer states that, although epidemiologic and clinical studies have methodological limitations including small sample size and study design, no retinal toxicity, ototoxicity, cardiotoxicity, or growth and developmental abnormalities have been observed in children who were exposed to hydroxychloroquine in utero.100
CDC states that pregnancy is not a contraindication to use of hydroxychloroquine when the drug is indicated for prevention of malaria.115 In addition, CDC states that recommendations for use of hydroxychloroquine for the treatment of uncomplicated malaria in pregnant women are the same as those for other patients.143
There is a pregnancy registry to monitor pregnancy outcomes in women exposed to hydroxychloroquine during pregnancy, and patients should be encouraged to enroll in the registry by calling 877-311-8972.100
Hydroxychloroquine is distributed into human milk in low concentrations.100 It is not known whether the drug has any effects on milk production.100
The manufacturer states that no adverse reactions have been reported in breast-fed infants of mothers who received hydroxychloroquine and no retinal toxicity, ototoxicity, cardiotoxicity, or growth and developmental abnormalities have been observed in children who were exposed to hydroxychloroquine through breast milk.100
The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for hydroxychloroquine and any potential adverse effects on the breast-fed child from the drug or from the underlying maternal condition.100
CDC states that the amount of drug present in human milk is insufficient to provide adequate protection against malaria in breast-feeding infants.115 If prevention of malaria is necessary, such infants should receive recommended dosages of appropriate antimalarial agent(s).115
Drugs that Prolong the QT Interval
Concomitant use of hydroxychloroquine and drugs known to prolong the QT interval may increase the risk of QT interval prolongation and ventricular arrhythmias.100 Concomitant use of hydroxychloroquine with drugs that potentially could prolong the QT interval or are arrhythmogenic is not recommended.100
Drugs that Lower the Seizure Threshold
Hydroxychloroquine can lower the seizure threshold and concomitant use with other antimalarials known to lower the seizure threshold (e.g., mefloquine) may increase the risk of seizures.100
In a study in healthy individuals, concomitant use of chloroquine and ampicillin decreased bioavailability of ampicillin.100 A similar interaction between hydroxychloroquine and ampicillin cannot be ruled out.100
Concomitant use of chloroquine and antacids can decrease absorption of chloroquine and an interval of at least 4 hours between administration of chloroquine and these drugs is recommended.100 A similar interaction between hydroxychloroquine antacids cannot be ruled out.100
Concomitant use of hydroxychloroquine and insulin or other antidiabetic agents may result in enhanced hypoglycemic effects and increase the risk of hypoglycemia.100 Decreased dosage of insulin or other antidiabetic drugs may be required in patients receiving hydroxychloroquine.100
The activity of antiepileptic agents might be impaired if administered concomitantly with hydroxychloroquine.100
Concomitant use of cimetidine resulted in a twofold increase in chloroquine exposure.100 A similar interaction between hydroxychloroquine and cimetidine cannot be ruled out, and concomitant use should be avoided.100
Concomitant use of hydroxychloroquine and cyclosporine has resulted in increased concentrations of cyclosporine.100 If the drugs are used concomitantly, serum cyclosporine concentrations should be monitored.100
Concomitant use of hydroxychloroquine and digoxin may result in increased serum digoxin concentrations.100 If the drugs are used concomitantly, serum digoxin concentrations should be monitored closely.100
Concomitant use of hydroxychloroquine and methotrexate may increase the incidence of adverse reactions.100
Concomitant use of chloroquine and praziquantel has been reported to decrease bioavailability of praziquantel.100 A similar interaction between hydroxychloroquine and praziquantel cannot be ruled out.100
Concomitant use of hydroxychloroquine and rifampin has resulted in lack of efficacy of hydroxychloroquine.100 Concomitant use of hydroxychloroquine and rifampin should be avoided.100
Concomitant use of hydroxychloroquine and drugs known to induce retinal toxicity (e.g., tamoxifen) may increase the risk of retinal damage.100
Hydroxychloroquine has an extremely narrow therapeutic range213 and overdosage of the drug has resulted in severe toxicity or death.100, 213 Symptoms of hydroxychloroquine overdosage may be apparent within 1-3 hours after ingestion.100 Cardiovascular toxicity, including QRS or QTc prolongation, ventricular tachycardia, ventricular fibrillation, torsades de pointes, atrioventricular block, cardiac arrest, and death have been reported.100 Life-threatening hypotension is common and, in severe toxicity, severe hypokalemia secondary to an intracellular shift occurs.100 In addition, CNS depression, seizures, visual disturbances, transient blindness, and coma may occur.100
If patients present within the first hour after ingestion of an overdosage of hydroxychloroquine, use of GI decontamination procedures should be considered.100 If the level of consciousness rapidly deteriorates in severe overdosage, intubation should be considered before GI decontamination procedures.100 Plasma potassium concentrations should be monitored and managed accordingly.100 Hemofiltration, hemodialysis, and hemoperfusion are not beneficial.100
For recommendations regarding management of hydroxychloroquine overdosage, consider contacting a poison center (800-221-2222) or medical toxicologist.100
The exact mechanism of the activity of hydroxychloroquine against Plasmodium is not known.100 Hydroxychloroquine is a weak base and may exert its effect by concentrating in acid vesicles of the parasite and inhibiting polymerization of heme.100 It also inhibits certain enzymes by interacting with DNA.100
The exact mechanism(s) underlying the anti-inflammatory and immunomodulatory effects of hydroxychloroquine in the treatment of rheumatoid arthritis, systemic lupus erythematosus, and chronic discoid lupus erythematosus have not been fully determined.100
Hydroxychloroquine has activity against Plasmodium , some other protozoa, and various bacteria, fungi, and viruses.213
Hydroxychloroquine, like chloroquine, is a blood schizonticidal agent and is active against asexual erythrocytic forms of susceptible Plasmodium malariae , P. ovale , P. vivax , and P. falciparum .100 The drug is not active against gametocytes and exoerythrocytic forms, including the hypnozoite liver stage forms of P. ovale and P. vivax .100
Resistance to 4-aminoquinoline derivatives (chloroquine and hydroxychloroquine) has been reported with increasing frequency in Plasmodium falciparum , and chloroquine-resistant P. falciparum is now found in all parts of the world where P. falciparum malaria occurs, except the Caribbean and Central America west of the Panama Canal.115
P. vivax with resistance or decreased susceptibility to chloroquine has been confirmed in Papua New Guinea and Indonesia.115, 121, 143 Chloroquine-resistant P. vivax also has been reported rarely in Burma (Myanmar), India, and Central and South America.143
Plasmodium with reduced susceptibility to chloroquine also have reduced susceptibility to hydroxychloroquine.100
To date, there has been no widespread evidence of chloroquine resistance in P. malariae , P. ovale , or P. knowlesi .143
Following a single 200-mg oral dose of hydroxychloroquine sulfate in healthy males, peak concentrations in whole blood of 129.6 ng/mL were attained at 3.3 hours and peak plasma concentrations of 50.3 ng/mL were attained at 3.7 hours.100 Following a single 200-mg dose of oral hydroxychloroquine sulfate, the mean fraction of the dose absorbed was 0.74 (compared to IV administration of 155-mg dose of hydroxychloroquine).100 Peak concentrations of metabolites in blood were observed at the same time as peak concentrations of hydroxychloroquine.100
In patients with rheumatoid arthritis receiving oral hydroxychloroquine, the fraction of the dose absorbed is highly variable (30-100%); mean hydroxychloroquine concentrations are significantly higher in those with less disease activity.100
Hydroxychloroquine has a large volume of distribution and is extensively distributed to tissues.100
Hydroxychloroquine readily crosses the placenta100 and is distributed into human milk in low concentrations.100, 102
Hydroxychloroquine is partially metabolized.100 The major metabolite in plasma and blood is desethylhydroxychloroquine (DHCQ); other metabolites include desethylchloroquine (DCQ) and bidesethylhydroxychloroquine (BDCQ).100, 109 Hydroxychloroquine and its metabolites are slowly excreted by the kidneys.109
The elimination half-life of hydroxychloroquine is prolonged.106 The drug has been reported to have a mean elimination half-life of about 40 days,100, 106 but considerable interindividual variation has been demonstrated.106
Following a single 200-mg oral dose in healthy males, a plasma half-life of 123.5 days was observed.100 Following chronic oral administration of hydroxychloroquine, the absorption half-life has been reported to be approximately 3-4 hours and the terminal half-life has ranged from 40-50 days.100
Hydroxychloroquine concentrations are still detectable in urine after 3 months; approximately 10% of the dose is eliminated as the parent drug.100
In patients with rheumatoid arthritis who received hydroxychloroquine for at least 6 months, renal clearance of the drug was similar to that reported when a single dose was administered to healthy volunteers, suggesting that there is no change in clearance of the drug with chronic dosing.100 Renal clearance of unchanged hydroxychloroquine was approximately 16-30%.100
Hydroxychloroquine is a synthetic antimalarial agent that is a 4-aminoquinoline derivative.100, 213 Hydroxychloroquine is the hydroxyl analog of chloroquine.213 Hydroxychloroquine is commercially available as the sulfate salt that occurs as a white or off-white, crystalline powder.100
Hydroxychloroquine sulfate tablets should be stored in tight, light-resistant containers at room temperature up to 30°C, but may be exposed to temperatures ranging from 15-30°C.100
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 200 mg (155 mg of hydroxychloroquine base)* | Hydroxychloroquine Sulfate Tablets | |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
100. Concordia. Plaquenil® (hydroxychloroquine sulfate) tablets prescribing information. Dublin 9, Ireland; 2021 May.
102. American Academy of Pediatrics Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics . 1989; 84:924-36. [PubMed 2677964]
103. Fraenkel L, Bathon JM, England BR et al. 2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Care Res (Hoboken) . 2021; 73:924-939. [PubMed 34101387]
106. Tett SE, Cutler DJ, Day RO et al. A dose-ranging study of the pharmacokinetics of hydroxy-chloroquine following intravenous administration to healthy volunteers. Br J Clin Pharmacol . 1988; 26:303-13. [PubMed 3179169]
109. McChesney EW. Animal toxicity and pharmacokinetics of hydroxychloroquine sulfate. Am J Med . 1983; 75(Suppl. 1A):11-8. [PubMed 6408923]
111. Raoult D, Houpikian P, Dupont HT et al. Treatment of Q fever endocarditis: comparison of 2 regimens containing doxycycline and ofloxacin or hydroxychloroquine. Arch Intern Med . 1999; 159:167-73. [PubMed 9927100]
112. Lupoglazoff JM, Brouqui P, Magnier S et al. Q fever tricuspid valve endocarditis. Arch Dis Child . 1997; 77:448-9. [PubMed 9487972][PubMedCentral]
113. US Centers for Disease Control and Prevention. Q fever—California, Georgia, Pennsylvania, and Tennessee, 2000-2001. MMWR Morb Mortal Wkly Rep . 2002; 51:924-5. [PubMed 12403408]
114. Bruce AJ, Ahmed I. Childhood-onset porphyria cutanea tarda: successful therapy with low-dose hydroxychloroquine (Plaquenil). J Am Acad Dermatol . 1998; 38(5 pt 2):810-3. [PubMed 9591792]
115. US Centers for Disease Control and Prevention. CDC health information for international travel, 2020. Atlanta, GA: US Department of Health and Human Services. Updates may be available at CDC website. [Web]
116. Wallace DJ. The use of chloroquine and hydroxychloroquine for non-infectious conditions other than rheumatoid arthritis or lupus: a critical review. Lupus . 1996; 5(Suppl 1):S59-64.
117. Petersen CS, Thomsen K. High-dose hydroxychloroquine treatment of porphyria cutanea tarda. J Am Acad Dermatol . 1992; 26:614-9. [PubMed 1597548]
121. . Advice for travelers. Med Lett Drugs Ther . 2019; 61:153-160. [PubMed 31599872]
122. US Centers for Disease Control and Prevention. Q fever: information for healthcare providers. From CDC website. Accessed 2021 Oct 11. [Web]
123. Stölzel U, Doss MO, Schuppan D. Clinical Guide and Update on Porphyrias. Gastroenterology . 2019; 157:365-381.e4. [PubMed 31085196]
134. Anon. Drugs for parasitic infections. Treat Guidel Med Lett . 2013; 11;e1-31. [Web]
143. US Centers for Disease Control and Prevention. Treatment of malaria: Guidelines for clinicians (United States). 2021 May 11. From CDC website. Updates may be available at CDC website. [Web]
144. US Centers for Disease Control and Prevention. Malaria in the United States: Treatment tables. From CDC website. Accessed 2021 Oct 11. Updates may be available at CDC website. [Web]
193. Devaux CA, Rolain JM, Colson P et al. New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19?. Int J Antimicrob Agents . 2020; In Press; :105938. [PubMed 32171740]
194. Cortegiani A, Ingoglia G, Ippolito M et al. A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19. J Crit Care . 2020; [PubMed 32173110]
197. 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; :105949. [PubMed 32205204]
198. 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; [PubMed 32150618]
200. U.S. National Library of Medicine. ClinicalTrials.gov. Accessed 2020 Mar 25. [Web]
212. Liu J, Cao R, Xu M et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov . 2020; 6:16. [PubMed 32194981]
213. Barber BE. Chloroquine and hydroxychloroquine. In: Grayson ML, ed. Kucers' the use of antibiotics: a clinical review of antibacterial, antifungal, antiparasitic, and antiviral drugs. 7th ed. Boca Raton, FL: CRC Press; 3030-46.
215. Sahraei Z, Shabani M, Shokouhi S et al. Aminoquinolines against coronavirus disease 2019 (COVID-19): chloroquine or hydroxychloroquine. Int J Antimicrob Agents . 2020; :105945. [PubMed 32194152]
216. 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; [PubMed 32196083]
218. Chen J, Liu D, Li L. A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19). J Zhejiang Univ . 2020;
221. Chinese Clinical Trial Registry. Accessed 2020 March 27. Available at [Web]/enindex.aspx.
222. US Centers for Disease Control and Prevention. Severe illness associated with using non-pharmaceutical chloroquine phosphate to prevent and treat coronavirus disease 2019 (COVID-19). 2020 Mar 28. From CDC Health Alert Network. [Web]
224. US Food and Drug Administration. Letter of authorization: Emergency use authorization for use of chloroquine phosphate or hydroxychloroquine sulfate supplied from the strategic national stockpile for treatment of 2019 Coronavirus disease. 2020 Mar 28. From FDA website. [Web]
230. US Food and Drug Administration. Letter regarding revocation of emergency use authorization (EUA) for emergency use of chloroquine phosphate and hydroxychloroquine sulfate supplied from the strategic national stockpile for treatment of 2019 Coronavirus disease. 2020 Jun 15. From FDA website. [Web]
231. National Institutes of Health. Coronavirus disease 2019 (COVID-19) treatment guidelines. From NIH website. Accessed 2021 Oct 11. Updates may be available at NIH website. [Web]
232. Infectious Diseases Society of America. IDSA guidelines on the treatment and management of patients with COVID-19. From IDSA website. Accessed 2021 Oct 11. Updates may be available at IDSA website [Web]