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Hydroxychloroquine

Pronunciation

Pronunciation

(hye droks ee KLOR oh kwin)

Index Terms

  • Hydroxychloroquine Sulfate

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral, as sulfate:

Plaquenil: 200 mg

Plaquenil: 200 mg [contains corn starch]

Generic: 200 mg

Brand Names: U.S.

  • Plaquenil

Pharmacologic Category

  • Aminoquinoline (Antimalarial)
  • Antimalarial Agent

Pharmacology

Interferes with digestive vacuole function within sensitive malarial parasites by increasing the pH and interfering with lysosomal degradation of hemoglobin; inhibits locomotion of neutrophils and chemotaxis of eosinophils; impairs complement-dependent antigen-antibody reactions

Absorption

Incomplete and variable (~70% [range: 25 to 100%]) (Tett 1993)

Metabolism

Hepatic; metabolites include bidesethylchloroquine, desethylhydroxychloroquine, and desethylchloroquine (McChesney 1966)

Excretion

Urine (15% to 25% [Tett 1993]; as metabolites and unchanged drug [up to 60%, McChesney 1966]); may be enhanced by urinary acidification

Onset of Action

Rheumatic disease: May require several weeks to respond

Half-Life Elimination

~40 days (Tett 1993)

Protein Binding

~40%, primarily albumin (Tett 1993)

Use: Labeled Indications

Lupus erythematosus: Treatment of chronic discoid erythematosus and systemic lupus erythematosus (SLE) in adults.

Malaria: Treatment of uncomplicated malaria caused by susceptible strains of Plasmodium vivax, P. malariae, P. ovale, and P. falciparum; prophylaxis of malaria in geographic areas where chloroquine resistance is not reported.

Limitations of use: Hydroxychloroquine is not effective against chloroquine or hydroxychloroquine-resistant malaria strains of Plasmodium species; not recommended for the treatment of complicated malaria, for malaria prophylaxis in regions with chloroquine resistance, or for treatment when the Plasmodium species has not been identified; hydroxychloroquine does not prevent relapses of P. vivax and P. ovale infections because it is not effective against the hypnozoite forms of these parasites.

Rheumatoid arthritis: Treatment of acute and chronic rheumatoid arthritis (RA) in adults.

Off Label Uses

Porphyria cutanea tarda

Data from a randomized, nonblinded pilot study supports the use of hydroxychloroquine in the treatment of porphyria cutanea tarda [Singal 2012]. Additional trials are necessary to further define the role of hydroxychloroquine in this condition.

Primary Sjögren Syndrome - extraglandular manifestations

Data from small noncontrolled studies have suggested benefit of hydroxychloroquine in the treatment of myalgia and arthralgia (extraglandular symptoms) of primary Sjögren syndrome. However, randomized, placebo-controlled trials demonstrated no significant improvement in symptoms associated with Sjögren syndrome, including fatigue and chronic pain. Inconsistent criteria for patient inclusion and patient response, small numbers of patients, and the abbreviated study length of some of the published studies may have contributed to the conflicting results. Additional trials are needed to define the role of hydroxychloroquine for extraglandular symptoms.

Q fever (chronic)

Based on the Centers for Disease Control and Prevention (CDC) recommendations for the diagnosis and management of Q fever (Coxiella burnetti), hydroxychloroquine (in combination with doxycycline) is effective and recommended for the treatment of chronic Q fever.

Contraindications

Known hypersensitivity to hydroxychloroquine, 4-aminoquinoline derivatives, or any component of the formulation.

Canadian labeling: Additional contraindications (not in the US labeling): Preexisting retinopathy; use in children <6 years or weighing <35 kg

Dosing: Adult

Note: Hydroxychloroquine sulfate 200 mg is equivalent to 155 mg hydroxychloroquine base and 250 mg chloroquine phosphate. All doses below expressed as hydroxychloroquine sulfate.

Lupus erythematosus (off-label dose): Oral: 200 to 400 mg daily as a single daily dose or in 2 divided doses (Lam 2016; Tsang-A-Sjoe 2015). Due to the risk of retinal toxicity, do not exceed a daily dose of 5 mg/kg/day using actual body weight or 400 mg (AAO [Marmor 2016]; Plaquenil PI)

Malaria, chemoprophylaxis: Oral:

Manufacturer’s labeling: 400 mg once weekly on same day each week; begin 2 weeks before exposure; if suppressive therapy is not begun prior to exposure, administer an initial loading dose of 800 mg in 2 divided doses, 6 hours apart; continue once weekly treatment for 8 weeks after leaving endemic area

Alternate dosing: 400 mg once weekly on the same day each week; begin 1 to 2 weeks before travel to malarious area, continue therapy while in malarious area and for 4 weeks after leaving the area (CDC 2016)

Malaria, acute attack: Oral: 800 mg initially, followed by 400 mg at 6, 24, and 48 hours

Rheumatoid arthritis (off-label dose): Oral: Initial: 400 mg daily as a single daily dose or in 2 divided doses, with or without concomitant non-biologic disease-modifying antirheumatic drugs (Kumar 2013; O’Dell 2013; Rath 2010; Smolen 2016); Maintenance: 300 mg daily (usually after 3 months of initial dosing) (Kumar 2013). Due to the risk of retinal toxicity, do not exceed a daily dose of 5 mg/kg/day using actual body weight or 400 mg (AAO [Marmor 2016]; Plaquenil PI).

Porphyria cutanea tarda (off-label use): Oral: 100 mg twice weekly; continue until plasma porphyrin levels are normal for at least one month (Singal 2012); however, additional data may be necessary to further define the role of hydroxychloroquine in this condition.

Primary Sjögren syndrome (extraglandular manifestations) (off-label use): Oral: Usual dose: 200 mg daily (Mavragani 2006). Note: Due to the risk of retinal toxicity, do not exceed a daily dose of 5 mg/kg/day using actual body weight or 400 mg (AAO [Marmor 2016]; Plaquenil PI).

Q fever, chronic (off-label use) (CDC 2013): Oral:

Endocarditis or vascular infection: 200 mg every 8 hours in combination with doxycycline for ≥18 months

Noncardiac organ disease: 200 mg every 8 hours in combination with doxycycline (duration based on serologic response; ID consult recommended)

Postpartum with serologic evidence present >12 months after delivery: 200 mg every 8 hours in combination with doxycycline for 12 months

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Hydroxychloroquine sulfate 200 mg is equivalent to 155 mg hydroxychloroquine base and 250 mg chloroquine phosphate. All doses below expressed as hydroxychloroquine sulfate.

Malaria, chemoprophylaxis: Infants, Children, and Adolescents: Oral:

Manufacturer’s labeling: 6.5 mg/kg once weekly (maximum: 400 mg/dose) on same day each week; begin 2 weeks before exposure; if suppressive therapy is not begun prior to exposure, administer an initial loading dose of 13 mg/kg (maximum dose: 800 mg) in 2 divided doses, 6 hours apart; continue once weekly treatment for 8 weeks after leaving endemic area

Alternate dosing: 6.5 mg/kg (maximum: 400 mg/dose) once weekly on the same day each week; begin 1 to 2 weeks before travel to malarious area, continue therapy while in malarious area and for 4 weeks after leaving the area (CDC 2016)

Malaria, acute attack: Infants, Children, and Adolescents: Oral: 13 mg/kg initially (maximum: 800 mg/dose), followed by 6.5 mg/kg (maximum: 400 mg/dose) at 6, 24, and 48 hours

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling; dosage reduction may be needed; use with caution.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling; use with caution.

Dosing: Obesity

Rheumatic diseases (eg, rheumatoid arthritis, lupus erythematosus, primary Sjögren syndrome [off-label use]): Available data do not specifically address dosing in obese patients; however, some experts recommend standard daily doses (non-weight-based) up to a maximum of 400 mg/day in patients weighing ≥80 kg.

Extemporaneously Prepared

A 25 mg/mL hydroxychloroquine sulfate oral suspension may be made with tablets. With a towel moistened with alcohol, remove the coating from fifteen 200 mg hydroxychloroquine sulfate tablets. Crush tablets in a mortar and reduce to a fine powder. Add 15 mL of Ora-Plus and mix to a uniform paste; add an additional 45 mL of vehicle and mix until uniform. Mix while adding sterile water for irrigation in incremental proportions to almost 120 mL; transfer to a calibrated bottle, rinse mortar with sterile water, and add sufficient quantity of sterile water to make 120 mL. Label "shake well". A 30-day expiration date is recommended, although stability testing has not been performed.

Pesko LJ, "Compounding: Hydroxychloroquine," Am Druggist, 1993, 207(4):57.

Administration

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

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from light.

Drug Interactions

Androgens: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Exceptions: Danazol. Monitor therapy

Anthelmintics: Aminoquinolines (Antimalarial) may decrease the serum concentration of Anthelmintics. Monitor therapy

Antidiabetic Agents: May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Antipsychotic Agents (Phenothiazines): Antimalarial Agents may increase the serum concentration of Antipsychotic Agents (Phenothiazines). Monitor therapy

Artemether: May enhance the adverse/toxic effect of Antimalarial Agents. Management: Artemether/Lumefantrine (combination product) should not be used with other antimalarials unless there is no other treatment option. Avoid combination

Beta-Blockers: Aminoquinolines (Antimalarial) may decrease the metabolism of Beta-Blockers. Exceptions: Atenolol; Carteolol (Ophthalmic); Levobunolol; Metipranolol; Nadolol; Sotalol. Monitor therapy

Cardiac Glycosides: Aminoquinolines (Antimalarial) may increase the serum concentration of Cardiac Glycosides. Monitor therapy

Dapsone (Systemic): May enhance the adverse/toxic effect of Antimalarial Agents. Specifically, concomitant use of dapsone with antimalarial agents may increase the risk for hemolytic reactions. Antimalarial Agents may enhance the adverse/toxic effect of Dapsone (Systemic). Specifically, concomitant use of antimalarial agents with dapsone may increase the risk of hemolytic reactions. Management: Closely monitor patients for signs/symptoms of hemolytic reactions with concomitant use of dapsone and antimalarial agents, particularly in patients deficient in glucose-6-phosphate dehydrogenase (G6PD), methemoglobin reductase, or with hemoglobin M. Consider therapy modification

Dapsone (Topical): Antimalarial Agents may enhance the adverse/toxic effect of Dapsone (Topical). Specifically, the risk of hemolytic reactions may be increased. Management: Closely monitor for signs/symptoms of hemolytic reactions with concomitant use of topical dapsone and antimalarial agents. Patients with glucose-6-phosphate dehydrogenase deficiency may be at particularly high risk for adverse hematologic effects. Consider therapy modification

Herbs (Hypoglycemic Properties): May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Highest Risk QTc-Prolonging Agents: Hydroxychloroquine may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Hypoglycemia-Associated Agents: May enhance the hypoglycemic effect of other Hypoglycemia-Associated Agents. Monitor therapy

Lumefantrine: Antimalarial Agents may enhance the adverse/toxic effect of Lumefantrine. Management: Artemether/Lumefantrine (combination product) should not be used with other antimalarials unless there is no other treatment option. Avoid combination

MAO Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Mefloquine: Aminoquinolines (Antimalarial) may enhance the adverse/toxic effect of Mefloquine. Specifically, the risk for QTc-prolongation and the risk for convulsions may be increased. Mefloquine may increase the serum concentration of Aminoquinolines (Antimalarial). Management: Avoid concurrent use, and delay administration of mefloquine until at least 12 hours after the last dose of an aminoquinoline antimalarial when possible. Avoid combination

Moderate Risk QTc-Prolonging Agents: Hydroxychloroquine may enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

Pegvisomant: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Prothionamide: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Quinolone Antibiotics: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolone Antibiotics may diminish the therapeutic effect of Blood Glucose Lowering Agents. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Monitor therapy

Salicylates: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Tamoxifen: May enhance the adverse/toxic effect of Hydroxychloroquine. Specifically, concomitant use of tamoxifen and hydroxychloroquine may increase the risk of retinal toxicity. Monitor therapy

Adverse Reactions

Frequency not defined:

Central nervous system: Ataxia, dizziness, emotional disturbance, emotional lability, headache, irritability, lassitude, nerve deafness, nervousness, nightmares, psychosis, seizure, suicidal tendencies, vertigo

Dermatologic: Acute generalized exanthematous pustulosis, alopecia, bleaching of hair, bullous rash, dyschromia (skin and mucosal; black-blue color), erythema (annulare centrifugum), erythema multiforme, exacerbation of psoriasis (nonlight sensitive), exfoliative dermatitis, lichenoid eruption, maculopapular rash, morbilliform rash, pruritus, skin photosensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria

Endocrine & metabolic: Exacerbation of porphyria, weight loss

Gastrointestinal: Anorexia, diarrhea, nausea, stomach cramps, vomiting

Hematologic & oncologic: Agranulocytosis, anemia, aplastic anemia, hemolysis (in patients with glucose-6-phosphate deficiency), leukopenia, purpuric rash, thrombocytopenia

Hepatic: Acute hepatic failure (rare), hepatic insufficiency (rare)

Hypersensitivity: Angioedema

Neuromuscular & skeletal: Myopathy (including palsy or neuromyopathy, leading to progressive weakness and atrophy of proximal muscle groups; may be associated with mild sensory changes, loss of deep tendon reflexes, and abnormal nerve conduction)

Ophthalmic: Accommodation disturbance, corneal changes (transient edema, punctate to lineal opacities, decreased sensitivity, deposits, visual disturbances, blurred vision, photophobia [reversible on discontinuation]), decreased visual acuity, macular edema, nystagmus, optic disk disorder (pallor/atrophy), retinal pigment changes, retinal vascular disease (attenuation of arterioles), retinitis pigmentosa, retinopathy (early changes reversible [may progress despite discontinuation if advanced]), scotoma, vision color changes, visual field defect

Otic: Tinnitus

Respiratory: Bronchospasm

Postmarketing and/or case reports (Limited to important or life-threatening): Cardiomyopathy, epithelial keratopathy (Dosso 2007), hypoglycemia (Cansu 2008; Unübol 2011), macular degeneration, maculopathy

Warnings/Precautions

Concerns related to adverse effects:

• Cardiovascular effects: Cardiomyopathy resulting in cardiac failure, sometimes fatal, has been reported (symptoms may present as atrioventricular block, pulmonary hypertension, sick sinus syndrome, or as cardiac complications), and may appear during acute or chronic therapy. Monitor for signs/symptoms of cardiac compromise; discontinue treatment promptly if signs and symptoms of cardiomyopathy occur. In a scientific statement from the American Heart Association, hydroxychloroquine has been determined to be an agent that may either cause direct myocardial toxicity or exacerbate underlying myocardial dysfunction (magnitude: major) (AHA [Page 2016]). Consider chronic toxicity if conduction disorders (eg, bundle branch block, atrioventricular heart block) as well as biventricular hypertrophy are diagnosed. May also be associated with QT interval prolongation; ventricular arrhythmia and torsades de pointes have been reported (avoid concurrent use of other medications which may prolong the QT interval).

• Dermatologic effects: Skin reactions to hydroxychloroquine may occur; use with caution in patients on concomitant medications with a propensity to cause dermatitis.

• Hematologic effects: Bone marrow suppression (eg, agranulocytosis, anemia, aplastic anemia, leukopenia, thrombocytopenia) have been reported; periodically monitor CBC during prolonged therapy. Discontinue treatment if signs/symptoms of severe blood disorder not attributable to the underlying disease occur.

• Hypoglycemia: Severe hypoglycemia, including life-threatening loss of consciousness, has been reported in patients with and without concomitant use of antidiabetic agents. Advise patients of risk of hypoglycemia and associated signs/symptoms; discontinue use in patients who develop severe hypoglycemia.

• Neuromuscular effects: Proximal myopathy or neuromyopathy, leading to progressive weakness, proximal muscle atrophy, depressed tendon reflexes, and abnormal nerve conduction may occur, especially with long-term therapy. Curvilinear bodies and muscle fiber atrophy with vacuolar changes have been noted on muscle or nerve biopsy. Muscle strength (especially proximal muscles) and reflexes should be assessed periodically during long term therapy.

• Psychiatric effects: Suicidal behavior has been reported rarely.

• Retinal toxicity: Retinal toxicity, potentially causing irreversible retinopathy, is predominantly associated with high daily doses and a duration of >5 years of use of chloroquine or hydroxychloroquine in the treatment of rheumatic diseases. Other major risk factors include concurrent tamoxifen use, renal impairment, lower body weight, and the presence of macular disease. Daily hydroxychloroquine (base) doses >5 mg/kg actual body weight were associated with an ~10% risk of retinal toxicity within 10 years of treatment and an almost 40% risk after 20 years of therapy. Risk is most accurately assessed on the basis of duration of use relative to daily dose/body weight (Marmor [AAO 2016]; Melles 2014). Based on these risks, the American Academy of Ophthalmology (AAO) recommends not exceeding a daily hydroxychloroquine dosage of 5 mg/kg using actual body weight. Previous recommendations to use ideal body weight are no longer advised; very thin patients in particular were at increased risk for retinal toxicity using this practice. Current AAO guidelines do not specifically address dosing in obese patients. AAO also recommends baseline screening for retinal toxicity and annual screening beginning after 5 years of use (or sooner if major risk factors are present) (Marmor [AAO 2016]). If ocular toxicity is suspected, discontinue and monitor closely; retinal changes and visual disturbances may progress after discontinuation. A baseline ocular exam is recommended within the first year of initiating hydroxychloroquine treatment.

Disease-related concerns:

• G6PD deficiency: Use with caution in patients with known G6PD deficiency; hemolysis may occur.

• Gastrointestinal disorders: Use with caution in patients with gastrointestinal disorders.

• Hepatic impairment: Use with caution in patients with hepatic impairment, alcoholism, or concurrent therapy with hepatotoxic agents.

• Porphyria: Use with extreme caution in patients with porphyria; may exacerbate or precipitate disease.

• Psoriasis: Use with extreme caution in patients with psoriasis; may exacerbate or precipitate disease.

• Renal impairment: Use with caution in patients with renal impairment; dosage reduction may be needed.

Special populations:

• Pediatric: Pediatric patients have an increased sensitivity to aminoquinolones. Safety and efficacy have not been established for chronic use in children for juvenile idiopathic arthritis or for systemic lupus erythematosus.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Monitoring Parameters

CBC at baseline and periodically; liver function; renal function (in patients at risk for ocular toxicity); blood glucose (if symptoms of hypoglycemia occur); muscle strength (especially proximal, as a symptom of neuromyopathy) during long-term therapy

Ophthalmologic exam at baseline (fundus examination within the first year plus visual fields and spectral-domain optical coherence tomography [SD OCT] if maculopathy is present) to screen for retinal toxicity, followed by annual screening beginning after 5 years of use (or sooner if major risk factors are present) (Marmor [AAO 2016]). Additionally, the manufacturer recommends an ocular exam include best corrected distance visual acuity and an automated threshold visual field of the central 10 degrees (24 degrees in patients of Asian ancestry as retinal toxicity may appear outside of the macula). Consider annual exams (without deferring 5 years) in patients with significant risk factors.

Pregnancy Considerations

Hydroxychloroquine can be detected in the cord blood at delivery in concentrations similar to those in the maternal serum (Costedoat-Chalumeau 2002). In animal reproduction studies with chloroquine, accumulation in fetal ocular tissues was observed and remained for several months following drug elimination from the rest of the body. Based on available human data, an increased risk of fetal ocular toxicity has not been observed following maternal use of hydroxychloroquine, but additional studies are needed to confirm (Osadchy 2011).

Maternal lupus is associated with adverse maternal and fetal events; however, pregnancy outcomes may be improved if conception does not occur until the disease has been inactive for ≥6 months. Hydroxychloroquine is one of the medications recommended for the management of lupus and lupus nephritis in pregnant women. If pregnancy is detected during therapy, it should not be stopped (could precipitate a flare in maternal disease and exposure to the fetus will still continue for 6 to 8 weeks due to tissue binding) (Baer 2011; Bertsias 2012; Hahn 2012; Levy 2001). Maternal use of hydroxychloroquine may also decrease the incidence of cardiac malformations associated with neonatal lupus (Izmirly 2012).

Malaria infection in pregnant women may be more severe than in nonpregnant women and has a high risk of maternal and perinatal morbidity and mortality. Therefore, pregnant women and women who are likely to become pregnant are advised to avoid travel to malaria-risk areas. Hydroxychloroquine is recommended as an alternative treatment of pregnant women for uncomplicated malaria in chloroquine-sensitive regions (refer to current guidelines) (CDC 2011).

Women exposed to hydroxychloroquine for the treatment of rheumatoid arthritis or systemic lupus erythematosus during pregnancy may be enrolled in the Organization of Teratology Information Specialists (OTIS) Autoimmune Diseases Study pregnancy registry (877-311-8972).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, anxiety, lack of appetite, weight loss, diarrhea, nausea, vomiting, or abdominal pain. Have patient report immediately to prescriber signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, tachycardia, confusion, increased hunger, or sweating), vision changes, bruising, bleeding, abnormal movements, twitching, difficulty swallowing, difficulty speaking, unable to control eye movements, seizures, mood changes, suicidal ideation, nightmares, hearing impairment, tinnitus, change in balance, chills, pharyngitis, muscle weakness, severe loss of strength and energy, tachycardia, abnormal heartbeat, severe dizziness, passing out, shortness of breath, excessive weight gain, swelling of arms or legs, or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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