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Hydroxychloroquine

Medically reviewed by Drugs.com. Last updated on Aug 5, 2020.

Pronunciation

(hye droks ee KLOR oh kwin)

Index Terms

  • Coronavirus
  • COVID-19
  • Hydroxychloroquine Sulfate

Dosage Forms

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

Tablet, Oral, as sulfate:

Plaquenil: 200 mg

Generic: 200 mg

Brand Names: U.S.

  • Plaquenil

Pharmacologic Category

  • Aminoquinoline (Antimalarial)
  • Antimalarial Agent

Pharmacology

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.

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 in adults.

Malaria: Treatment of uncomplicated malaria caused by susceptible strains of Plasmodium vivax, Plasmodium malariae, Plasmodium ovale, and Plasmodium falciparum; prophylaxis of malaria in geographic areas where chloroquine resistance is not reported. Note: The CDC guidelines also recommend hydroxychloroquine for chloroquine-sensitive Plasmodium knowlesi malaria (CDC 2020c).

Limitations of use: Hydroxychloroquine is not effective against chloroquine- or hydroxychloroquine-resistant malaria strains of Plasmodium species; not recommended for treatment of complicated malaria, malaria prophylaxis in regions with chloroquine resistance, or treatment when the Plasmodium species has not been identified; hydroxychloroquine alone 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 in adults.

Off Label Uses

Dermatomyositis, cutaneous disease

Data from case reports and retrospective and open-label studies support the use of hydroxychloroquine in the treatment of cutaneous manifestations of dermatomyositis [Cosnes 1995], [Olson 1989], [Woo 1984].

Porphyria cutanea tarda

Data from a randomized, nonblinded pilot study support the use of hydroxychloroquine in the treatment of porphyria cutanea tarda [Singal 2012].

Primary Sjögren syndrome (extraglandular manifestations)

Data from a small noncontrolled study have suggested benefit of hydroxychloroquine in the treatment of myalgia and arthralgia (extraglandular symptoms) of primary Sjögren syndrome [Fox 1996]. 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 [Gottenberg 2014], [Kruize 1993].

Q fever (Coxiella burnetii)

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

Sarcoidosis, arthropathy

Clinical experience supports the use of hydroxychloroquine in the treatment of sarcoid arthropathy [ASG [Agarwal] 2018], [Sequeira 2019].

Sarcoidosis, cutaneous disease (extensive)

Data from case series and retrospective and open-label studies support the use of hydroxychloroquine in the treatment of extensive cutaneous sarcoidosis [Chong 2005], [Jones 1990], [Modi 2008].

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: Coronavirus disease 2019 (COVID-19): Although hydroxychloroquine has been under investigation for use in the treatment and prophylaxis of COVID-19 (see http://www.ClinicalTrials.gov) and an emergency use authorization (EUA) was issued by the FDA in March 2020, the FDA subsequently revoked the EUA in June 2020 due to safety concerns and lack of efficacy, citing the benefits no longer outweigh the risks for the authorized use (FDA 2020). National Institutes of Health guidelines recommend against the use of hydroxychloroquine for the treatment of COVID-19 in hospitalized patients and only recommend use in nonhospitalized patients as part of a clinical trial (NIH 2020).

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) (AAO [Marmor 2016]; Travassos 2019). 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 (Wallace 2020).

Dermatomyositis, cutaneous disease (off-label use): Note: Used in combination with antipruritic medications, topical therapy, and nonpharmacologic measures (eg, photoprotection) (Miller 2019; Vleugels 2020).

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 (Ang 2005; James 1985; Miller 2019; Vleugels 2020; Woo 1984). 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 (AAO [Marmor 2016]; Melles 2014; Petri 2019; Wallace 2020; manufacturer's labeling).

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 (Lam 2016; Tsang-A-Sjoe 2015; Wallace 2020).

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 (AAO [Marmor 2016]; Melles 2014; Petri 2019; Wallace 2020; manufacturer's labeling).

Discoid lupus erythematosus and subacute cutaneous lupus erythematosus: For use if response to local therapy is inadequate or impractical due to widespread skin lesions (Clarke 2020; Kuhn 2017):

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 (AAO [Marmor 2016]; Melles 2014; Petri 2019; Wallace 2020; manufacturer's labeling).

Malaria (alternative agent):

Prophylaxis: Note: Only for use in individuals traveling to malarious regions without chloroquine resistance (CDC Yellow Book 2020).

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 (CDC Yellow Book 2020).

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 or tafenoquine. Not recommended for treatment if chloroquine or hydroxychloroquine was given for chemoprophylaxis (CDC 2020c; WHO 2015).

Oral: 800 mg once, followed by 400 mg at 6, 24, and 48 hours after initial dose (total dose: 2 g) (CDC 2020c; WHO 2015).

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 (Singal 2012; Singal 2019).

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) (Carsons 2017; Demarchi 2017; Fox 1996; Kruize 1993; Mavragani 2006); some experts also use in patients with major salivary enlargement resulting in cosmetic concerns or glandular pain (Baer 2019).

Oral: Initial: 200 to 400 mg daily as a single daily dose or in 2 divided doses (Gottenberg 2014; Kruize 1993; Mavragani 2006). 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 (AAO [Marmor 2016]; Melles 2014; Petri 2019; Wallace 2020; manufacturer's labeling).

Q fever (Coxiella burnetii) (off-label use):

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 (CDC [Anderson 2013]; Raoult 2020).

Prevention of persistent infection following acute Q fever: Note: Generally reserved for patients with valvulopathy/cardiomyopathy (CDC [Anderson 2013]; Million 2013; Raoult 2020) or postpartum women with persistent serologic evidence of infection >12 months after delivery (CDC [Anderson 2013]).

Oral: 600 mg/day in 1 or 3 divided doses in combination with doxycycline for 12 months (CDC [Anderson 2013]; Million 2013; Raoult 2020).

Rheumatoid arthritis: Note: May be used as monotherapy (alternative agent) in patients with mild or limited disease without poor prognostic factors. May also be used in patients with moderate to severe disease regardless of prognostic factors in combination with other nonbiologic disease-modifying antirheumatic drugs (ACR [Singh 2016]; EULAR [Smolen 2014]; Kumar 2013; O’Dell 2013; Rath 2010; Smolen 2016).

Oral: 200 to 400 mg daily as a single daily dose or in 2 divided doses (Kumar 2013). 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 (AAO [Marmor 2016]; Melles 2014; Petri 2019; Wallace 2020; manufacturer's labeling).

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 (ASG [Agarwal] 2018; Sequeira 2019).

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 (Sequeira 2019). 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 (AAO [Marmor 2016]; Melles 2014; Petri 2019; Wallace 2020; manufacturer's labeling).

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 (Modi 2008; Prystowsky 2019). 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 (AAO [Marmor 2016]; Melles 2014; Petri 2019; Wallace 2020; manufacturer's labeling).

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

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Although hydroxychloroquine has been under investigation for use in the treatment and prophylaxis of coronavirus disease 2019 (COVID-19) (see ClinicalTrials.gov) and an emergency use authorization (EUA) was issued by the FDA in March 2020, the FDA subsequently revoked the EUA in June 2020 due to safety concerns and lack of efficacy, citing the benefits no longer outweigh the risks for the authorized use (FDA 2020). Hydroxychloroquine is not recommended for the treatment of COVID-19 in hospitalized patients and should only be used in nonhospitalized patients as part of a clinical trial (Chiotos 2020; NIH 2020).

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) (AAO [Marmor 2016]).

Malaria:

Chemoprophylaxis: Note: Only for use in individuals traveling to malarious regions without chloroquine resistance (CDC 2020).

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 (CDC 2020).

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, tafenoquine) (CDC 2020).

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 (CARRA [Kim 2017]; Kliegman 2020; Olson 1989); however, some experts recommend a maximum of 5 mg/kg/day to mitigate risk of retinal toxicity (AAO [Marmor 2016]). Use in combination with nonpharmacologic measures (eg, photoprotection), topical therapies, and/or other systemic therapies (CARRA [Kim 2017]; Kliegman 2020; Olson 1989).

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 (EULAR [Fanouriakis 2019]; Marks 2010; Thorbinson 2016); based upon data in adults, some experts recommend a maximum of 5 mg/kg/day to mitigate risk of retinal toxicity (AAO [Marmor 2016]); Costedoat-Chalemeau 2019; EULAR [Fanouriakis 2019]; Fanouriakis 2020).

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

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 (Wallace 2020).

Extemporaneously Prepared

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.

Administration

Oral: Administer with food or milk. Do not crush or divide film-coated tablets per the manufacturer; the tablets have a bitter taste (McLaughlin 1991). 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 (CDC 2020a), or an extemporaneous suspension may be compounded (See Extemporaneously Prepared).

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 Agents with Blood Glucose Lowering Effects. Exceptions: Danazol. 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

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). Monitor therapy

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

CycloSPORINE (Systemic): Hydroxychloroquine may increase the serum concentration of CycloSPORINE (Systemic). 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

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

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

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

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

Maitake: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. 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

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

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

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

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

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

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

1% to 10%: Ophthalmic: Retinopathy (4%; serum concentration dependent [Petri 2019]; 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:

Dermatologic: Acute generalized exanthematous pustulosis (Charfi 2015), alopecia (Sharma 2020), bullous rash, dyschromia (skin and mucosal), erythema multiforme, exacerbation of psoriasis, exfoliative dermatitis, hair discoloration, pruritus, skin photosensitivity (Sharma 2020), skin rash (Borik 2019), Stevens-Johnson syndrome (Leckie 2002), toxic epidermal necrolysis (Lateef 2009), urticaria

Endocrine & metabolic: Exacerbation of porphyria, weight loss

Gastrointestinal: Abdominal pain, decreased appetite, diarrhea, nausea, vomiting

Hematologic & oncologic: Agranulocytosis, anemia, aplastic anemia, bone marrow failure, leukopenia, thrombocytopenia

Hepatic: Abnormal hepatic function tests, acute hepatic failure

Hypersensitivity: Angioedema

Immunologic: Drug reaction with eosinophilia and systemic symptoms (Volpe 2008)

Nervous system: Ataxia, dizziness, emotional lability, fatigue, headache, irritability, nervousness, nightmares, psychosis (Das 2014), seizure, sensorineural hearing loss, suicidal tendencies (Mascolo 2018; Pinho de Oliveira Ribeiro 2013), vertigo

Neuromuscular & skeletal: Asthenia, myopathy (including paralysis or neuromyopathy, leading to progressive weakness and atrophy of proximal muscle groups; may be associated with mild sensory changes and loss of deep tendon reflexes; Casado 2006)

Ophthalmic: Corneal changes (corneal edema, corneal opacity, corneal sensitivity, corneal deposits, visual disturbance, blurred vision, photophobia), decreased visual acuity, macular degeneration, maculopathy, nystagmus disorder, retinal pigment changes, retinitis pigmentosa, scotoma, vision color changes, visual field defect

Otic: Deafness, tinnitus

Respiratory: Bronchospasm

Postmarketing:

Cardiovascular: Cardiomyopathy (AHA [Page 2016]; Tönnesmann 2012; Tönnesmann 2013), prolonged QT interval on ECG (Chen 2006; Stas 2008), torsades de pointes, ventricular arrhythmia

Dermatologic: Hyperpigmentation (Bahloul 2017; Sharma 2020)

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

Hematologic & oncologic: Neutropenia (FDA Safety Alert, April 1, 2020), pancytopenia (FDA Safety Alert, April 1, 2020)

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)

Ophthalmic: Epithelial keratopathy (Dosso 2007)

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

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 (monitor QT-prolonging effects during therapy in at-risk patients or if used in combination with other medications that 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. One study suggested a correlation of higher serum concentrations of hydroxychloroquine with ocular toxicity (Petri 2019). 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 in most patients. 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: Although the manufacturer's labeling recommends hydroxychloroquine be used with caution in patients with G6PD deficiency due to a potential for hemolytic anemia, there is 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 (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 US) (Mohammad 2017). In addition, the ACR Rheumatology guidelines do not mention the need to evaluate G6PD levels prior to initiation of therapy (Singh 2016).

• 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.

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

• 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 aminoquinolines.

Monitoring Parameters

CBC (with differential) 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; in patients at risk of torsades de pointes, monitor ECG at baseline and periodically during therapy to assess for QTc prolongation.

Ophthalmologic exam at baseline (fundus examination within the first year plus visual fields and spectral-domain optical coherence tomography 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.

Reproductive Considerations

Hydroxychloroquine is recommended for use in females with rheumatic and musculoskeletal diseases who are planning a pregnancy. Conception should be planned during a period of quiescent/low disease activity (ACR [Sammaritano 2020]). Females treated with hydroxychloroquine for lupus nephritis should continue treatment while planning a pregnancy; conception may be considered in stable patients after 6 months of inactive disease (EULAR/ERA-EDTA [Bertsias 2012]).

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 males 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 (Birru Talabi 2020; Costedoat-Chalumeau 2003; Diav-Citrin 2013). 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; EULAR/ERA-EDTA [Bertsias 2012]; Hahn 2012; Izmirly 2012; Levy 2001; Petri 2019; Tunks 2013).

Available guidelines recommend treatment with hydroxychloroquine for systemic lupus erythematosus (SLE) and lupus nephritis (LN) during pregnancy. Hydroxychloroquine may be beneficial for some pregnant women with antiphospholipid syndrome (ACR [Sammaritano 2020]; EULAR [Andreoli 2017]; EULAR/ERA-EDTA [Bertsias 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. When travel is unavoidable, pregnant women 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 2020c).

Due to pregnancy-induced physiologic changes, some pharmacokinetic properties of hydroxychloroquine may be altered in pregnant women; 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 women with SLE, but there was no association between disease activity, pregnancy outcomes, and hydroxychloroquine blood levels in pregnant women 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.

Hydroxychloroquine has been under evaluation for the management of coronavirus disease 2019 (COVID-19). An emergency use authorization (EUA) was issued by the FDA in April 2020 authorizing use of hydroxychloroquine for hospitalized patients. It was revoked in June 2020 amidst concerns for safety and lack of efficacy. Hydroxychloroquine should only be given as part of a clinical trial. Pregnant women were not included in the first reported study and outcome data related to pregnancy are limited (FDA 2020; Gautret 2020; HHS 2020; Pereira 2020; Pierce-Williams 2020).

Data collection to monitor pregnancy and infant outcomes following exposure to hydroxychloroquine is ongoing. 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).

In addition, data collection to monitor pregnancy and infant outcomes following exposure to COVID-19 is ongoing. Health care providers are encouraged to enroll females exposed to COVID-19 during pregnancy in the OTIS pregnancy registry (1-877-311-8972; https://mothertobaby.org/join-study/) or the PRIORITY (Pregnancy CoRonavIrus Outcomes RegIsTrY) (1-415-754-3729; https://priority.ucsf.edu/).

Patient Education

What is this drug used for?

• It is used to treat or prevent malaria.

• It is used to treat lupus.

• It is used to treat rheumatoid arthritis.

• It may be given to you for other reasons. Talk with the doctor.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Dizziness

• Fatigue

• Headache

• Anxiety

• Lack of appetite

• Weight loss

• Diarrhea

• Skin discoloration

• Hair discoloration

• Hair loss

• Nausea

• Vomiting

• Abdominal pain

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes

• Low blood sugar like dizziness, headache, fatigue, feeling weak, shaking, fast heartbeat, confusion, increased hunger, or sweating

• Infection

• Vision changes

• Blurred vision

• Bruising

• Bleeding

• Abnormal movements

• Unable to control eye movements

• Seizures

• Mood changes

• Thoughts of suicide

• Nightmares

• Hearing loss

• Change in hearing

• Noise or ringing in the ears

• Change in balance

• Tremors

• Muscle weakness

• Severe loss of strength and energy

• Fast heartbeat

• Abnormal heartbeat

• Heart problems like cough or shortness of breath that is new or worse, swelling of the ankles or legs, abnormal heartbeat, weight gain of more than five pounds in 24 hours, dizziness, or passing out

• Stevens-Johnson syndrome/toxic epidermal necrolysis like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in mouth, throat, nose, or eyes

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Hydroxychloroquine sulfate FDA fact sheets – Health care provider; Patient

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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