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Hydroxychloroquine: Pediatric drug information

Hydroxychloroquine: Pediatric drug information
(For additional information see "Hydroxychloroquine: Drug information" and see "Hydroxychloroquine: Patient drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
Brand Names: US
  • Plaquenil
Brand Names: Canada
  • APO-Hydroxyquine;
  • JAMP Hydroxychloroquine Sulf;
  • MINT-Hydroxychloroquine;
  • NRA-Hydroxychloroquine;
  • Plaquenil;
  • PRO-Hydroxychloroquine-200 [DSC]
Therapeutic Category
  • Antimalarial Agent;
  • Antirheumatic, Disease Modifying
Dosing: Pediatric

Note: All doses below expressed as hydroxychloroquine sulfate. Hydroxychloroquine sulfate 200 mg is equivalent to 155 mg hydroxychloroquine base. To avoid retinopathy and permanent vision loss, do not exceed recommended maximum doses. Baseline and periodic screening for retinopathy is necessary for rheumatologic uses and in long-term therapy (eg, >1 to 5 years depending on patient risk factors) (Ref).

Malaria

Malaria:

Chemoprophylaxis: Note: Only for use in individuals traveling to malarious regions without chloroquine resistance (Ref).

Infants, Children, and Adolescents: Oral: 6.5 mg/kg hydroxychloroquine sulfate once weekly on the same day each week; maximum dose: 400 mg/dose hydroxychloroquine sulfate; begin 1 to 2 weeks before travel to malarious area; continue while in malarious area and for 4 weeks after leaving the area (Ref).

Treatment, uncomplicated: Infants, Children, and Adolescents: Oral: Initial: 12.9 mg/kg/dose hydroxychloroquine sulfate (maximum initial dose: 800 mg/dose hydroxychloroquine sulfate); followed by 6.5 mg/kg hydroxychloroquine sulfate at 6, 24, and 48 hours after initial dose; maximum dose: 400 mg/dose hydroxychloroquine sulfate. For infection caused by Plasmodium vivax or Plasmodium ovale, use in combination with appropriate antirelapse treatment (ie, primaquine) (Ref).

Juvenile dermatomyositis, skin predominant

Juvenile dermatomyositis, skin predominant: Limited data available: Children and Adolescents: Oral: 5 mg/kg/day in 1 to 2 divided doses; maximum daily dose: 400 mg/day. Dosage range reported: 2 to 6 mg/kg/day (Ref); however, some experts recommend a maximum of 5 mg/kg/day to mitigate risk of retinal toxicity (Ref). Use in combination with nonpharmacologic measures (eg, photoprotection), topical therapies, and/or other systemic therapies (Ref).

Systemic lupus erythematosus

Systemic lupus erythematosus (SLE): Limited data available: Children and Adolescents: 4 to 6.5 mg/kg/day in 1 to 2 divided doses; maximum daily dose: 400 mg/day (Ref); based upon data in adults, some experts recommend a maximum of 5 mg/kg/day to mitigate risk of retinal toxicity (Ref).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Pediatric

Altered kidney function: Infants, Children, and Adolescents:

Note: Renal clearance accounts for 15% to 25% of total clearance (Ref).

Mild to severe impairment: There are no dosage adjustments provided in the manufacturer's labeling; use with caution. Dosage adjustment may be considered with chronic use.

Hemodialysis: Not dialyzable (Ref): There are no dosage adjustments provided in the manufacturer's labeling; use with caution. Dosage adjustment may be considered with chronic use.

Peritoneal dialysis: There are no dosage adjustments provided in the manufacturer's labeling; use with caution. Dosage adjustment may be considered with chronic use.

Continuous renal replacement therapy (CRRT): Unlikely to be dialyzable based on wide volume of distribution and high lipophilicity (Ref): There are no dosage adjustments provided in the manufacturer's labeling; use with caution. Dosage adjustment may be considered with chronic use.

Dosing: Hepatic Impairment: Pediatric

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

Dosing: Adult

(For additional information see "Hydroxychloroquine: Drug information")

Note: Dosage forms: Variable daily dosing (eg, alternating or skipping doses on certain days each week) may be used to obtain the recommended dose for rheumatologic uses. All doses below are expressed as hydroxychloroquine sulfate salt. Hydroxychloroquine sulfate salt 200 mg is equivalent to hydroxychloroquine base 155 mg. Safety: To avoid retinopathy and permanent vision loss, do not exceed recommended maximum doses. Baseline and periodic screening for retinopathy is necessary for rheumatologic uses and in long-term therapy (eg, >1 to 5 years depending on patient risk factors) (Ref). To mitigate risk of cardiac arrhythmias, correct electrolyte imbalances prior to use. Tolerability: GI upset (nausea, vomiting, diarrhea) is a common adverse effect. Dividing doses, taking with food, and, if appropriate, gradual dose escalation (in treating rheumatologic diseases) may improve tolerability (Ref).

Dermatomyositis, cutaneous

Dermatomyositis, cutaneous (off-label use): Note: Used in combination with antipruritic medications, topical therapy, and nonpharmacologic measures (eg, photoprotection) (Ref).

Oral: 300 to 400 mg daily as a single daily dose or in 2 divided doses. Assess response after 3 months; may attempt to slowly taper after several months of satisfactory response (Ref). Note: Due to the risk of retinal toxicity, most patients should not receive a daily dose >5 mg/kg/day using actual body weight or 400 mg, whichever is lower (Ref).

Lupus erythematosus

Lupus erythematosus:

Systemic lupus erythematosus: Note: In general, hydroxychloroquine (or chloroquine) is indicated for all patients with systemic disease; additional therapy is individualized according to predominant disease manifestations and activity (Ref).

Oral: 200 to 400 mg daily as a single daily dose or in 2 divided doses. Note: Due to the risk of retinal toxicity, most patients should not receive a daily dose >5 mg/kg/day using actual body weight or 400 mg, whichever is lower (Ref).

Discoid lupus erythematosus and subacute cutaneous lupus erythematosus: For use if response to local therapy is inadequate or impractical due to widespread skin lesions (Ref):

Oral: 200 to 400 mg daily as a single daily dose or in 2 divided doses. Note: Due to the risk of retinal toxicity, most patients should not receive a daily dose >5 mg/kg/day using actual body weight or 400 mg, whichever is lower (Ref).

Malaria

Malaria (alternative agent):

Prophylaxis: Note: Only for use in individuals traveling to malarious regions without chloroquine resistance (Ref).

Oral: 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 (Ref).

Treatment, uncomplicated: Note: Only for treatment of nonsevere infections caused by chloroquine-sensitive malaria; for infection caused by Plasmodium vivax or Plasmodium ovale, give in combination with primaquine. Not recommended for treatment if chloroquine or hydroxychloroquine was given for chemoprophylaxis (Ref).

Oral: 800 mg once, followed by 400 mg at 6, 24, and 48 hours after initial dose (total dose: 2 g) (Ref).

Porphyria cutanea tarda

Porphyria cutanea tarda (off-label use): Oral: 100 mg twice weekly; continue until plasma or urine porphyrin levels are normal for at least several months (Ref).

Primary Sjögren syndrome

Primary Sjögren syndrome (off-label use): Note: For treatment of moderate to severe extraglandular manifestations (eg, arthralgias, myalgias, fatigue) or milder symptoms unresponsive to nonpharmacologic measures and nonsteroidal anti-inflammatory drugs (NSAIDs) (Ref); some experts also use in patients with major salivary enlargement resulting in cosmetic concerns or glandular pain (Ref).

Oral: Initial: 200 to 400 mg daily as a single daily dose or in 2 divided doses (Ref). Note: Due to the risk of retinal toxicity, most patients should not receive a daily dose >5 mg/kg/day using actual body weight or 400 mg, whichever is lower (Ref).

Q fever

Q fever (Coxiella burnetii) (off-label use): Note: Given higher dose recommendations for Q fever, the CDC recommends routine therapeutic drug monitoring and ophthalmic exams for retinal toxicity (Ref).

Persistent localized infection (eg, endocarditis, osteomyelitis, vascular infection, prosthetic joint infection) in nonpregnant patients: Oral: 600 mg/day in 1 or 3 divided doses in combination with doxycycline for ≥18 months, depending on site of infection and serologic response; in prosthetic valve disease or vascular infection, extend treatment to ≥24 months (Ref).

Prevention of persistent infection following acute Q fever: Note: Generally reserved for patients with valvulopathy/cardiomyopathy or antiphospholipid antibodies (Ref) or postpartum women with persistent serologic evidence of infection >12 months after delivery (Ref).

Oral: 600 mg/day in 1 or 3 divided doses in combination with doxycycline for 12 months; patients with detectable antiphospholipid antibodies should receive treatment until levels normalize (Ref).

Rheumatoid arthritis

Rheumatoid arthritis: Note: For use as monotherapy in disease-modifying antirheumatic drug (DMARD)–naive patients with low disease activity. May also be used as part of alternative combination therapy (with other nonbiologic DMARDs) in patients with moderate to severe disease whose treatment targets have not been met despite maximally tolerated methotrexate therapy (Ref).

Oral: 200 to 400 mg daily as a single daily dose or in 2 divided doses (Ref). Note: Due to the risk of retinal toxicity, most patients should not receive a daily dose >5 mg/kg/day using actual body weight or 400 mg, whichever is lower (Ref).

Sarcoidosis

Sarcoidosis (off-label use):

Arthropathy: Note: As additional therapy for NSAID-resistant symptoms in patients with an inadequate response to glucocorticoids or who are unable to fully taper (Ref).

Oral: 200 to 400 mg daily as a single daily dose or in 2 divided doses. Therapy may be continued for ~1 year and then gradually tapered in patients who have responded and are stable on therapy (Ref). Note: Due to the risk of retinal toxicity, most patients should not receive a daily dose >5 mg/kg/day using actual body weight or 400 mg, whichever is lower (Ref).

Cutaneous disease, extensive: Oral: 200 to 400 mg daily as a single daily dose or in 2 divided doses for ≥3 months to evaluate for efficacy; if there is satisfactory improvement, may consider gradual tapering and discontinuation if response is maintained (Ref). Note: Due to the risk of retinal toxicity, most patients should not receive a daily dose >5 mg/kg/day using actual body weight or 400 mg, whichever is lower (Ref).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.

Mild to severe impairment: There are no specific dosage adjustments provided in the manufacturer's labeling; however, dosage reduction may be needed with prolonged use (eg, systemic lupus erythematosus) (Ref); use with caution. With short-term use at recommended doses and durations (eg, malaria treatment), no dosage adjustment necessary (Ref).

Hemodialysis: Not dialyzable (Ref): There are no specific dosage adjustments provided in the manufacturer's labeling; however, dosage reduction may be needed with prolonged use (eg, systemic lupus erythematosus) (Ref); use with caution. With short-term use at recommended doses and durations (eg, malaria treatment), no dosage adjustment necessary (Ref).

Peritoneal dialysis: There are no specific dosage adjustments provided in the manufacturer's labeling; however, dosage reduction may be needed with prolonged use (eg, systemic lupus erythematosus) (Ref); use with caution. With short-term use at recommended doses and durations (eg, malaria treatment), no dosage adjustment necessary (Ref).

CRRT: Unlikely to be dialyzable (Ref): There are no specific dosage adjustments provided in the manufacturer's labeling; however, dosage reduction may be needed with prolonged use (eg, systemic lupus erythematosus) (Ref); use with caution. With short-term use at recommended doses and durations (eg, malaria treatment), no dosage adjustment necessary (Ref).

Dosing: Hepatic Impairment: Adult

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

Dosage Forms: US

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

Tablet, Oral, as sulfate:

Plaquenil: 200 mg [contains corn starch]

Generic: 100 mg, 200 mg, 300 mg, 400 mg

Generic Equivalent Available: US

Yes

Dosage Forms: Canada

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

Tablet, Oral, as sulfate:

Plaquenil: 200 mg

Generic: 200 mg

Administration: Pediatric

Oral: Administer with food or milk. Do not crush or divide film-coated tablets per the manufacturer; the tablets have a bitter taste (Ref). In patients unable to swallow tablets, it has been recommended that tablets may be crushed and mixed with a small amount of applesauce, chocolate syrup, or jelly (Ref), or an extemporaneous suspension may be compounded (See Extemporaneous Preparations).

Administration: Adult

Oral: Administer with food or milk. Do not crush or divide film-coated tablets per the manufacturer; the tablets have a bitter taste (Ref). In patients unable to swallow tablets, it has been recommended that tablets may be crushed and mixed with a small amount of applesauce, chocolate syrup, or jelly (Ref), or an extemporaneous suspension may be compounded (See Extemporaneously Prepared).

Storage/Stability

Store up to 30°C (86°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from light.

Use

Prophylaxis or treatment of acute uncomplicated malaria (FDA approved in pediatric patients [age not specified] and adults); treatment of systemic lupus erythematosus (SLE) (FDA approved in adults) and acute or chronic rheumatoid arthritis (FDA approved in adults); has also been used for juvenile dermatomyositis.

Medication Safety Issues
Sound-alike/look-alike issues:

Hydroxychloroquine may be confused with hydrocortisone, hydroxyurea

Plaquenil may be confused with Platinol

Adverse Reactions (Significant): Considerations
Cardiomyopathy

A predominantly restrictive or diastolic cardiomyopathy presenting as heart failure has been reported following long-term use of antimalarials for rheumatic diseases (especially chloroquine but occasionally hydroxychloroquine); systolic impairment may also occur (Ref). Additionally, conduction abnormalities (eg, atrioventricular block, sick sinus syndrome, bundle branch block) and pulmonary hypertension have been reported (Ref). On imaging, myocardial hypertrophy is most common in patients who develop cardiomyopathy. Clinicians should note that some patients may not have any or very few clinical symptoms. Laboratory findings may include elevated creatine kinase, lactate dehydrogenase, and/or troponins (Ref). While some patients may experience improvement following discontinuation, others experience permanent damage that may result in the need for cardiac transplant or death (Ref).

Mechanism: Time-related; exact mechanism is unknown. Hydroxychloroquine is hypothesized to bind to phospholipids within the myocyte, leading to accumulation in lysosomes and inhibiting lysosomal enzymes in several tissues, including peripheral nerve, cardiac, and skeletal muscle. The resulting intracellular degradation leads to accumulation of metabolic products (eg, phospholipids, glycogen) (Ref).

Onset: Delayed (Ref); patients may remain clinically asymptomatic for a long period of time with symptoms only appearing at a later stage and/or with high cumulative doses (eg, several years of therapy) (Ref). Some patients may experience improvement within 1 month to 1 year following discontinuation, others experience permanent damage that may result in the need for cardiac transplant or death (Ref).

Risk factors:

The following confers an increased risk (Ref):

• Longer duration of therapy

• Higher cumulative doses

• Older age

• Females

• Preexisting cardiac disease

• Kidney impairment

G6PD deficiency

Although the manufacturer's labeling recommends that hydroxychloroquine be used with caution in patients with glucose-6-phospate deficiency (G6PD) due to the potential for hemolysis (hemolytic anemia), there are limited data to support this risk. Many experts consider hydroxychloroquine, when given in usual therapeutic doses to WHO Class II and III G6PD deficient patients, to probably be safe (Ref). In a retrospective chart review, no incidence of hemolytic anemia was found among the 11 patients identified with G6PD deficiency receiving hydroxychloroquine therapy, despite >700 months of exposure (all patients were African-American and located in the US) (Ref). In addition, the ACR Rheumatology guidelines do not mention the need to evaluate G6PD levels prior to initiation of therapy (Ref).

Hypersensitivity reactions (delayed)

Cutaneous hypersensitivity reactions ranging from maculopapular rash to severe cutaneous adverse reactions (SCARs) may occur. Various delayed, nonlife-threatening reactions have been reported, including lichenoid, urticarial, and maculopapular eruptions (Ref). Reported SCARs include acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS [also known as drug hypersensitivity syndrome]), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) (Ref). Hydroxychloroquine is also associated with phototoxic and photoallergic dermatitis (Ref).

Mechanism: Non-dose related; immunologic; delayed hypersensitivity reactions are mediated by T-cells or antibodies other than immunoglobulin E (IgE) (eg, IgG-mediated, such as some cytopenias) (Ref). SCARs are delayed type IV hypersensitivity reactions involving a T-cell mediated drug-specific immune response (Ref).

Onset: Varied; most nonlife-threatening cutaneous reactions occurred 5 to 14 days after initiation of hydroxychloroquine (Ref). Onset of SCARs is generally days to weeks after administration of the causative drug (Ref) but may occur more rapidly (usually within 1 to 4 days) upon reexposure (Ref).

Risk factors:

• Prior hypersensitivity reaction to 4-aminioquinolines. Note: There is conflicting evidence regarding cross-reactivity between the 4-aminoquinolines (eg, chloroquine, hydroxychloroquine), although most reports suggest tolerance of chloroquine in patients with nonsevere cutaneous reactions to hydroxychloroquine (Ref).

• Patients with dermatomyositis, in particular those with anti-small ubiquitin-like modifier 1 activating enzyme (anti-SAE-1/2) autoantibodies (Ref).

Hypoglycemia

Severe hypoglycemia has rarely been reported in patients (both with and without diabetes) who were receiving hydroxychloroquine (Ref).

Mechanism: Dose-related; related to the pharmacologic action. Chloroquine has been shown to reduce intracellular insulin degradation, increase intracellular insulin accumulation, slow receptor recycling, stimulate insulin-mediated glucose transport, and increase peripheral insulin sensitivity and secretion (Ref).

Onset: Unknown. In one case report, a patient was initiated on hydroxychloroquine and presented to the emergency department 2 months later with symptoms secondary to severe hypoglycemia (Ref).

Risk factors:

• Concomitant use of other medications known to lower blood glucose concentrations

Neuromuscular effects

Skeletal muscle myopathy or neuropathy leading to asthenia and atrophy of proximal muscle groups, depressed tendon reflexes, and abnormal nerve conduction have been reported (Ref). Symptoms ranged from painless proximal weakness in both upper and lower extremities to severe weakness requiring hospitalization and ventilatory support (Ref). Clinicians should note that patients with rheumatic disease may experience symptoms of their underlying disease that make diagnosis of myopathy difficult (Ref).

Mechanism: Time-related; exact mechanism is unknown. Hydroxychloroquine is hypothesized to bind to phospholipids within the myocyte, accumulating in lysosomes and inhibiting lysosomal enzymes in several tissues, including peripheral nerve, cardiac, and skeletal muscle. The resulting intracellular degradation leads to accumulation of metabolic products (eg, phospholipids, glycogen) (Ref). Muscle and nerve biopsies have been associated with curvilinear bodies and muscle fiber atrophy with vacuolar changes (Ref).

Onset: Delayed; varies from <1 year of therapy to >10 years (Ref). In addition, the response to discontinuation of hydroxychloroquine varies with some patients experiencing resolution of symptoms within weeks to months while others experience progression of symptoms (Ref).

Risk factors:

Risk factors are poorly defined but may include:

• White people (Ref)

• Kidney failure (Ref)

• Concomitant use of other myotoxic drugs, including corticosteroids (Ref)

Neuropsychiatric effects

Various neuropsychiatric effects have been described with antimalarial agents, including hydroxychloroquine. Symptoms have included hallucination, psychosis, psychomotor agitation, suicidal ideation, and suicidal tendencies (Ref).

Mechanism: Time-related; exact mechanism is not fully understood. Proposed hypotheses include a cholinergic imbalance related to the inhibition of the acetylcholinesterase, prostaglandin E antagonism, the accumulation of toxic metabolites in the lysosome, and the down-regulation of glycoprotein-P in the blood brain barrier (Ref).

Onset: Varied; reported onset varies greatly from weeks to years (Ref). One case report of psychiatric symptoms following use of chloroquine demonstrated that symptoms may persist for several months (Ref).

Risk factors:

• Family history of neuropsychiatric symptoms (Ref)

• Female patients (Ref)

• Concomitant administration of drugs known to increase hydroxychloroquine concentrations (Ref)

• Concomitant use of glucocorticoids (Ref)

• Concomitant use of alcohol (Ref)

• Low body weight (Ref)

QT prolongation

Long-term use or high doses of antimalarials (especially chloroquine but also hydroxychloroquine) have been associated with prolonged QT interval on ECG and subsequent ventricular arrhythmias (including torsades de pointes [TdP]), syncope, and sudden cardiac death (Ref).

Mechanism: Dose-related; exact mechanism is unknown. Hydroxychloroquine is hypothesized to abnormally affect ion currents (including hyperpolarization activated ion channels, delayed rectifier potassium currents, and L-type calcium ion currents). This may cause delayed depolarization and prolonged repolarization of cardiac myocytes, which can lead to QT interval prolongation (Ref).

Onset: Varied; effect is concentration-dependent; therefore, timing may be impacted by high doses or accumulation. In one study in healthy subjects administered chloroquine (100 mg base per day; n=3), QT prolongation was noted on day 3 of administration (Ref)

Risk factors:

In general, risk factors for drug-induced QT prolongation include:

• Females (Ref)

• Structural heart disease (eg, history of myocardial infarction or heart failure) (Ref)

• Genetic defects of cardiac ion channels (Ref)

• Congenital long QT syndrome (Ref)

• Baseline QTc interval prolongation (eg, >450 msec) (Ref)

• Electrolyte disturbances (eg, hypokalemia or hypomagnesemia) (Ref)

• Bradycardia (Ref)

• Hepatic impairment (Ref)

• Kidney impairment (Ref)

• Coadministration of multiple medications that prolong the QT interval or drug interactions that increase serum concentration of QT-prolonging medications (Ref)

Retinal toxicity

Long-term use of hydroxychloroquine may result in retinopathy characterized by parafoveal retinal damage (Ref). The clinical picture is classically characterized as a bilateral “bull's-eye” maculopathy; visual acuity generally remains intact until more severe damage has been realized. As retinopathy progresses, the area of functional deficit may expand to the foveal center with decreased visual acuity, peripheral vision, and night vision; cystoid macular edema may also occur. Clinicians should note that some patients may not experience symptoms during the early stages of retinopathy and that retinopathy is irreversible (Ref).

Mechanism: Time-related; exact mechanism is not fully understood. A proposed mechanism is impaired lysosomal degradation of photoreceptor outer segments by the retinal pigment epithelium (Ref).

Onset: Delayed; most commonly occurring >5 years after initiation of therapy (Ref).

Risk factors:

• High daily doses relative to body weight (≥5 mg/kg actual body weight) and a duration of >5 years of use in the treatment of rheumatic diseases (Ref)

• Higher serum concentrations of hydroxychloroquine (Ref)

• Concurrent tamoxifen use (Ref)

• Kidney impairment (Ref)

• Lower body weight (Ref)

• Preexisting macular disease (Ref)

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

1% to 10%: Ophthalmic: Retinopathy (4%; serum concentration dependent [Petri 2020b]; early changes reversible [may progress despite discontinuation if advanced])

<1%: Hematologic & oncologic: Hemolysis (rare; primarily a theoretical concern in patients with glucose-6-phosphate deficiency; data do not support withholding therapy in these patients [Luzzato 2016; Mohammad 2018])

Frequency not defined:

Cardiovascular: Sick sinus syndrome

Dermatologic: Exacerbation of psoriasis, exfoliative dermatitis, hair discoloration, pruritus, urticaria

Endocrine & metabolic: Weight loss

Gastrointestinal: Abdominal pain, anorexia

Hematologic & oncologic: Anemia, aplastic anemia, bone marrow depression, leukopenia, thrombocytopenia

Hepatic: Abnormal hepatic function tests

Hypersensitivity: Angioedema

Nervous system: Ataxia, dizziness, emotional lability, fatigue, headache, irritability, nervousness, nightmares, seizure, vertigo

Ophthalmic: Corneal changes (corneal edema, corneal opacity), nystagmus disorder, ophthalmic signs and symptoms (decreased dark adaptation)

Respiratory: Bronchospasm

Postmarketing:

Cardiovascular: Atrioventricular block (Bae 2012), bundle branch block (Costedoat-Chalumeau 2007), cardiomyopathy (AHA [Page 2016]; Fiehn 2020; Tönnesmann 2012; Tönnesmann 2013), heart failure (Figliozzi 2021), prolonged QT interval on ECG (Chatre 2018; Chen 2006; O’Laughlin 2016; Stas 2008), torsades de pointes (Chatre 2018; O’Laughlin 2016), ventricular arrhythmia (Chatre 2018; O’Laughlin 2016), ventricular tachycardia (Abdelmaseih 2020)

Dermatologic: Acute generalized exanthematous pustulosis (Charfi 2015; Soria 2015), alopecia (Sharma 2020), erythema multiforme (Abou Assalie 2017), erythroderma (Pai 2017), hyperpigmentation (Bahloul 2017; Sharma 2020), skin photosensitivity (Sharma 2020), skin rash (Borik 2019), Stevens-Johnson syndrome (Leckie 2002), toxic epidermal necrolysis (Lateef 2009; Soria 2015)

Endocrine & metabolic: Hypoglycemia (including severe hypoglycemia; Cansu 2008; FDA Safety Alert, April 1, 2020; Shojania 1999; Unübol 2011)

Gastrointestinal: Abdominal cramps (Abdelmaseih 2020), diarrhea (can be severe) (Abdelmaseih 2020), nausea (Abdelmaseih 2020), vomiting (Abdelmaseih 2020)

Genitourinary: Proteinuria

Hematologic & oncologic: Agranulocytosis (Andrès 2017), neutropenia (FDA Safety Alert, April 1, 2020), pancytopenia (FDA Safety Alert, April 1, 2020), thrombotic thrombocytopenia purpura (Arikan 2020)

Hepatic: Acute hepatic failure (Makin 1994)

Hypersensitivity: Drug reaction with eosinophilia and systemic symptoms (Soria 2015; Volpe 2008)

Nervous system: Confusion (FDA Safety Alert, April 1, 2020), delirium (FDA Safety Alert, April 1, 2020), extrapyramidal reaction (FDA Safety Alert, April 1, 2020), hallucination (Das 2014; FDA Safety Alert, April 1, 2020), psychomotor agitation (FDA Safety Alert, April 1, 2020; Manzo 2017), psychosis (Das 2014), suicidal ideation (Mascolo 2018; Pinho de Oliveira Ribeiro 2013), suicidal tendencies (Mascolo 2018; Pinho de Oliveira Ribeiro 2013)

Neuromuscular & skeletal: Myopathy (including paralysis 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; Casado 2006)

Ophthalmic: Blurred vision (Wang 2021), corneal deposits (Grierson 1997), decreased visual acuity (Eldeeb 2018), epithelial keratopathy (Dosso 2007), macular degeneration (Wang 2021), maculopathy (Warner 2001), photophobia (Grierson 1997), retinal pigment changes (Stelton 2013), scotoma (Eldeeb 2018, Stelton 2013), vision color changes (Stelton 2013), visual disturbance (Grierson 1997), visual field defect (Warner 2001)

Otic: Sensorineural hearing loss (Fernandes 2018), tinnitus (Fernandes 2018)

Renal: Renal insufficiency (FDA Safety Alert, April 1, 2020)

Respiratory: Pulmonary hypertension (Bae 2012)

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

Warnings/Precautions

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with hepatic impairment; dosage reduction may be needed.

• Myasthenia gravis: Use with caution in patients with myasthenia gravis; may exacerbate condition (Jallouli 2012; MGFA 2020).

• Porphyria: Avoid use in patients with porphyria unless benefits outweigh risks; may exacerbate or precipitate disease.

• Psoriasis: Avoid use in patients with psoriasis unless benefits outweigh risks; may exacerbate or precipitate disease.

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

Special populations:

• Glucose-6-phosphate dehydrogenase deficiency: Although the manufacturer's labeling recommends hydroxychloroquine be used with caution in patients with G6PD deficiency due to a potential for hemolytic anemia, there are limited data to support this risk. Many experts consider hydroxychloroquine, when given in usual therapeutic doses to the World Health Organization Class II and III G6PD deficient patients, to probably be safe (Cappellini 2008; Luzzatto 2016; Youngster 2010). In a retrospective chart review, no incidence of hemolytic anemia was found among the 11 patients identified with G6PD deficiency receiving hydroxychloroquine therapy, despite >700 months of exposure (all patients were African American and located in the United States) (Mohammad 2018). In addition, the American College of Rheumatology guidelines for the treatment of rheumatoid arthritis do not mention the need to evaluate G6PD levels prior to initiation of therapy (ACR [Fraenkel 2021]).

• Pediatric: Pediatric patients have an increased sensitivity to aminoquinolines.

Metabolism/Transport Effects

Substrate of CYP2D6 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program

Agalsidase Alfa: Hydroxychloroquine may diminish the therapeutic effect of Agalsidase Alfa. Risk C: Monitor therapy

Agalsidase Beta: Hydroxychloroquine may diminish the therapeutic effect of Agalsidase Beta. Risk C: Monitor therapy

Androgens: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

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

Artemether and Lumefantrine: Antimalarial Agents may enhance the adverse/toxic effect of Artemether and Lumefantrine. Management: Artemether/lumefantrine (combination product) should not be used with other antimalarials unless there is no other treatment option. If combined, monitor patients for increased toxicities of both agents, including QTc interval prolongation. Risk D: Consider therapy modification

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

ChlorproMAZINE: Antimalarial Agents may increase the serum concentration of ChlorproMAZINE. Risk C: Monitor therapy

Cimetidine: May increase the serum concentration of Hydroxychloroquine. Risk X: Avoid combination

Ciprofloxacin (Systemic): Hydroxychloroquine may enhance the hyperglycemic effect of Ciprofloxacin (Systemic). Hydroxychloroquine may enhance the hypoglycemic effect of Ciprofloxacin (Systemic). Hydroxychloroquine may enhance the QTc-prolonging effect of Ciprofloxacin (Systemic). Risk C: Monitor therapy

Citalopram: May enhance the hypoglycemic effect of Hydroxychloroquine. Hydroxychloroquine may enhance the QTc-prolonging effect of Citalopram. Risk C: Monitor therapy

CycloSPORINE (Systemic): Hydroxychloroquine may increase the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy

Dapsone (Systemic): 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. 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. 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. Risk D: 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. Risk D: Consider therapy modification

Escitalopram: May enhance the hypoglycemic effect of Hydroxychloroquine. Hydroxychloroquine may enhance the QTc-prolonging effect of Escitalopram. Risk C: Monitor therapy

Gemifloxacin: Hydroxychloroquine may enhance the hyperglycemic effect of Gemifloxacin. Hydroxychloroquine may enhance the hypoglycemic effect of Gemifloxacin. Hydroxychloroquine may enhance the QTc-prolonging effect of Gemifloxacin. Risk C: Monitor therapy

Haloperidol: QT-prolonging Agents (Indeterminate Risk - Avoid) may enhance the QTc-prolonging effect of Haloperidol. Risk C: Monitor therapy

Herbal Products with Glucose Lowering Effects: May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Risk C: Monitor therapy

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

Levofloxacin-Containing Products (Systemic): Hydroxychloroquine may enhance the hyperglycemic effect of Levofloxacin-Containing Products (Systemic). Hydroxychloroquine may enhance the hypoglycemic effect of Levofloxacin-Containing Products (Systemic). Hydroxychloroquine may enhance the QTc-prolonging effect of Levofloxacin-Containing Products (Systemic). Risk C: Monitor therapy

Levoketoconazole: QT-prolonging Agents (Indeterminate Risk - Avoid) may enhance the QTc-prolonging effect of Levoketoconazole. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

Maitake: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: 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. Management: Avoid concurrent use, and delay administration of mefloquine until at least 12 hours after the last dose of an aminoquinoline antimalarial. Risk X: Avoid combination

Metoprolol: Hydroxychloroquine may increase the serum concentration of Metoprolol. Risk C: Monitor therapy

Monoamine Oxidase Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

Moxifloxacin (Systemic): Hydroxychloroquine may enhance the hyperglycemic effect of Moxifloxacin (Systemic). Hydroxychloroquine may enhance the hypoglycemic effect of Moxifloxacin (Systemic). Hydroxychloroquine may enhance the QTc-prolonging effect of Moxifloxacin (Systemic). Risk C: Monitor therapy

Pegvisomant: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

Prothionamide: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Avoid) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

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

Rabies Vaccine: Aminoquinolines (Antimalarial) may diminish the therapeutic effect of Rabies Vaccine. Management: If coadministration is unavoidable during rabies post-exposure vaccination, give a 5th dose of the rabies vaccine. If coadministration is unavoidable during rabies pre-exposure vaccination, ensure antibody titers are greater than or equal to 0.5 IU/mL. Risk D: Consider therapy modification

Remdesivir: Hydroxychloroquine may diminish the therapeutic effect of Remdesivir. Risk X: Avoid combination

Salicylates: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

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

Sparfloxacin: Hydroxychloroquine may enhance the hyperglycemic effect of Sparfloxacin. Hydroxychloroquine may enhance the hypoglycemic effect of Sparfloxacin. Hydroxychloroquine may enhance the QTc-prolonging effect of Sparfloxacin. Risk C: 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. Risk C: Monitor therapy

Reproductive Considerations

Hydroxychloroquine is recommended for use in patients with rheumatic and musculoskeletal diseases who are planning to become pregnant. Conception should be planned during a period of quiescent/low disease activity (ACR [Sammaritano 2020]).

Information related to paternal use of hydroxychloroquine is limited; however, available data have not shown hydroxychloroquine adversely impacts male fertility or increases the risk of adverse pregnancy outcomes when used prior to conception (Bermas 2019; Mouyis 2019). Hydroxychloroquine is recommended for use in patients with rheumatic and musculoskeletal diseases who are planning to father a child (ACR [Sammaritano 2020]).

Pregnancy Considerations

Hydroxychloroquine can be detected in the cord blood at delivery in concentrations similar to those in the maternal serum (Costedoat-Chalumeau 2002).

Adverse perinatal outcomes have not been associated with daily maternal doses of hydroxychloroquine ≤400 mg (Bérard 2021; Birru Talabi 2020; Costedoat-Chalumeau 2003; Diav-Citrin 2013; Huybrechts 2020). Retinal toxicity is a known risk following long-term use or high doses of hydroxychloroquine. Although animal reproduction studies have shown accumulation of chloroquine in fetal ocular tissues, an association between hydroxychloroquine and fetal ocular toxicity has not been confirmed in available human studies (Gaffar 2019; Levy 2001; Motta 2005; Osadchy 2011).

Maternal lupus is associated with adverse maternal and fetal events. If pregnancy is detected during therapy, hydroxychloroquine should not be stopped; cessation of hydroxychloroquine could precipitate a flare in maternal disease. Continued treatment is needed to control maternal disease and decrease the risk of maternal thrombosis and congenital heart block (Baer 2011; Izmirly 2012; Levy 2001; Petri 2020a; Tunks 2013).

Available guidelines recommend treatment with hydroxychloroquine for systemic lupus erythematosus (SLE) during pregnancy. Hydroxychloroquine may be beneficial for some pregnant patients with antiphospholipid syndrome (ACR [Sammaritano 2020]; EULAR [Andreoli 2017]).

Malaria infection in pregnant patients may be more severe than in nonpregnant patients and has a high risk of maternal and perinatal morbidity and mortality. Therefore, pregnant patients and patients who are likely to become pregnant are advised to avoid travel to malaria-risk areas. When travel is unavoidable, pregnant patients should take precautions to avoid mosquito bites and use effective prophylactic medications. Hydroxychloroquine is recommended for the treatment of uncomplicated malaria during pregnancy in chloroquine-sensitive regions (refer to current guidelines) (CDC 2020).

Due to pregnancy-induced physiologic changes, some pharmacokinetic properties of hydroxychloroquine may be altered during pregnancy; however, dosage adjustments are not needed (Balevic 2019b). In one study, hydroxychloroquine concentrations ≤100 ng/mL correlated with increased disease activity and adverse maternal/fetal outcomes in patients with SLE, but there was no association between disease activity, pregnancy outcomes, and hydroxychloroquine blood levels in pregnant patients under treatment for LN (Balevic 2019a). Due to tissue binding, if hydroxychloroquine is discontinued, it would take 6 to 8 weeks to be completely eliminated.

Data collection to monitor pregnancy and infant outcomes following exposure to hydroxychloroquine is ongoing. Patients exposed to hydroxychloroquine while pregnant are encouraged to enroll in the pregnancy registry (1-877-311-8972).

Monitoring Parameters

Note: Determinants for laboratory testing (ie, specific tests to monitor and how frequently) should take into consideration patient's clinical status and duration of therapy. Laboratory monitoring may be unnecessary in patients receiving short-term therapy.

CBC and platelet count with differential, liver function, and renal function at baseline and periodically during therapy; blood glucose (if symptoms of hypoglycemia occur); muscle strength (especially proximal) and deep tendon reflexes during prolonged therapy; monitor ECG at baseline and as clinically indicated in patients at elevated risk of QTc prolongation.

Ophthalmologic exam within the first year of prolonged or high-dose treatment (fundus examination plus visual fields and spectral-domain optical coherence tomography if maculopathy is present) to screen for retinal toxicity, followed by annual screening beginning after 3 to 5 years of use (or sooner if major risk factors are present) (AAO [Marmor 2016]; WHO 2012).

Mechanism of Action

Antimalarial: 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.

Pharmacokinetics (Adult data unless noted)

Onset of action: Rheumatic disease: May require several weeks to respond

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

Protein binding: ~40%, primarily albumin (Tett 1993)

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

Half-life elimination: ~40 days (Tett 1993)

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

Extemporaneous Preparations

25 mg/mL Oral Suspension

A 25 mg/mL hydroxychloroquine sulfate oral suspension may be made with tablets. Crush fifteen 200 mg hydroxychloroquine sulfate tablets in a mortar and reduce to a fine powder. Add small portions of Oral Mix (or Oral Mix SF) and mix to a uniform paste; mix while adding the vehicle in incremental portions to almost 120 mL; transfer to a graduated cylinder. Rinse mortar and pestle with vehicle and to graduated cylinder; add sufficient quantity of vehicle to make 120 mL. Transfer into an amber bottle. Label "shake well". Stable for 112 days at room temperature or refrigerated.

McHenry AR, Wempe MF, Rice PJ. Stability of extemporaneously prepared hydroxychloroquine sulfate 25-mg/mL suspensions in plastic bottles and syringes. Int J Pharm Compd. 2017;21(3):251-254.28557788

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.
Pricing: US

Tablets (Hydroxychloroquine Sulfate Oral)

100 mg (per each): $2.24

200 mg (per each): $0.40 - $4.36

300 mg (per each): $6.72

400 mg (per each): $8.96

Tablets (Plaquenil Oral)

200 mg (per each): $0.18

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Brand Names: International
  • Advaquenil (JO);
  • Axokine (AR);
  • Chloguin (TW);
  • Dimard (CO, EC);
  • Dolquine (ES, LB);
  • Duloc (KR);
  • Duroc (KR);
  • Ercoquin (DK);
  • Evoquin (AR, UY);
  • Fen Le (CN);
  • Futarhomal (EG);
  • Geniquin (TW);
  • Haloxin (SG);
  • HCQS (IN, PE, TH, ZW);
  • Hequinel (AU);
  • Hydroquin (TH);
  • Hydroquine (TW);
  • Hyquin (BD, LK);
  • Ilinol (CL);
  • Immard (UA);
  • Maquil (TW);
  • Metirel (UY);
  • Oxcq (LK);
  • Oxiklorin (FI, KR);
  • Planil (BD);
  • Plaquenil (CR, CY, DO, EG, GB, GT, HU, IS, JP, KW, LT, LU, LV, MX, NI, PA, QA, RO, SA, SG, SV, UA, VN);
  • Plaquenil Sulfate (AR, AU, BB, BE, BF, BG, BJ, BM, BS, BZ, CH, CI, CZ, DK, EE, ET, FR, GH, GM, GN, GR, GY, HK, HN, IE, IL, IT, JM, KE, LR, MA, ML, MR, MT, MU, MW, MY, NE, NG, NL, NO, NZ, PH, RU, SC, SD, SE, SK, SL, SN, SR, TH, TN, TR, TT, TW, TZ, UG, ZA, ZM);
  • Plaquinol (BR, CL, CO, EC, PE, PT, PY, VE);
  • Quinoric (MT);
  • Reconil (BD);
  • Reuquinol (BR);
  • Roquin (BD);
  • Supretic (PY);
  • Winflam (LK);
  • Yuma (KR);
  • Zyq (LK)


For country code abbreviations (show table)
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