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Hydroxychloroquine

Pronunciation

Pronunciation

(hye droks ee KLOR oh kwin)

Index Terms

  • Hydroxychloroquine Sulfate

Dosage Forms

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

Tablet, Oral, as sulfate:

Plaquenil: 200 mg [contains corn starch]

Generic: 200 mg

Brand Names: U.S.

  • Plaquenil

Pharmacologic Category

  • Aminoquinoline (Antimalarial)
  • Antimalarial Agent

Pharmacology

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

Absorption

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

Metabolism

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

Excretion

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

Onset of Action

Rheumatic disease: May require several weeks to respond

Half-Life Elimination

~40 days (Tett 1993)

Protein Binding

~40%, primarily albumin (Tett 1993)

Use: Labeled Indications

Lupus erythematosus: Treatment of chronic discoid and systemic lupus erythematosus (SLE) in patients who have not responded satisfactorily to drugs with less potential for serious adverse effects.

Malaria: Treatment of acute attacks and prophylaxis of malaria caused by Plasmodium vivax, P. malariae, P. ovale, and susceptible strains of P. falciparum.

Rheumatoid arthritis: Treatment of rheumatoid arthritis (RA) in patients who have not responded satisfactorily to drugs with less potential for serious adverse effects.

Contraindications

Hypersensitivity to hydroxychloroquine, 4-aminoquinoline derivatives, or any component of the formulation; retinal or visual field changes attributable to 4-aminoquinolines; long-term use in children

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

Dosing: Adult

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

Malaria, chemoprophylaxis: Oral:

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

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

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

Rheumatoid arthritis: Oral: Initial: 400 to 600 mg daily; increase dose gradually until optimum response level is reached; usually after 4 to 12 weeks dose should be reduced by 50% to a maintenance dose of 200 to 400 mg daily in 1 to 2 divided doses (O’Dell 2001; O’Dell 2002) .

Lupus erythematosus: Oral: 400 mg once or twice daily for several weeks to months depending on response; 200 to 400 mg daily in 1 to 2 divided doses (Costedoat-Chalumeau 2006; Wozniacka 2005) for prolonged maintenance therapy

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

Primary Sjögren syndrome (extraglandular manifestations) (off-label use): Oral: 6 to 7 mg/kg/day (Fox 1996); usual dose: 400 mg once daily (Marmor 2011). Note: Doses up to 6.5 mg/kg/day using ideal body weight or up to 5 mg/kg/day using actual body weight are associated with a low risk of retinopathy for up to 10 years (Melles 2014).

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

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

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

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

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

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

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

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

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

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

Dosing: Renal Impairment

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

Dosing: Hepatic Impairment

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

Extemporaneously Prepared

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

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

Administration

Administer with food or milk.

Dietary Considerations

May be taken with food or milk.

Storage

Store at 15°C and 30°C (59°F and 86°F).

Drug Interactions

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

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

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

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

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

Dapsone (Systemic): 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. 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

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

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

Adverse Reactions

Frequency not defined.

Cardiovascular: Cardiomyopathy (rare, relationship to hydroxychloroquine unclear)

Central nervous system: Ataxia, dizziness, emotional disturbance, headache, irritability, lassitude, nerve deafness, nervousness, nightmares, psychosis, seizure, suicidal tendencies (children may be more susceptible), vertigo

Dermatologic: Alopecia, bleaching of hair, bullous rash (including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, photosensitivity, exfoliative dermatitis), dyschromia (skin and mucosal; black-blue color), exacerbation of psoriasis (nonlight sensitive), pruritus, urticaria

Endocrine & metabolic: Exacerbation of porphyria, weight loss

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

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

Hepatic: Hepatic insufficiency (hepatic failure; isolated cases)

Hypersensitivity: Angioedema

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

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

Otic: Tinnitus

Respiratory: Bronchospasm, respiratory failure (myopathy-related)

Postmarketing and/or case reports: Hypoglycemia (Cansu, 2008; Unübol, 2011), keratopathy (Dosso, 2007)

ALERT: U.S. Boxed Warning

Experienced physician:

Health care providers should completely familiarize themselves with the complete contents of the package insert before prescribing hydroxychloroquine.

Warnings/Precautions

Concerns related to adverse effects:

• Cardiovascular effects: Cardiomyopathy resulting in cardiac failure, sometimes fatal, has been reported with high daily doses; discontinue treatment if signs and symptoms of cardiomyopathy occur. Consider chronic toxicity if conduction disorders (eg, bundle branch block, atrioventricular heart block) as well as biventricular hypertrophy are diagnosed. May also cause arrhythmia.

• Extrapyramidal reactions: Extrapyramidal reactions have been reported; symptoms may persist after discontinuation.

• 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 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 and symptoms; discontinue use in patients who develop severe hypoglycemia.

• Neuromuscular effects: Myopathy, neuromyopathy, palsies and progressive weakness may occur, especially with long-term therapy; muscle strength (especially proximal muscles) and reflexes should be assessed periodically during long term therapy. Myopathy may be reversible after discontinuation of therapy, but recovery may be prolonged. If weakness occurs, discontinue therapy. Use with caution in patients with neurological disorders.

• Psychiatric effects: Suicidal behavior has been reported rarely.

• Retinal toxicity: Retinal toxicity, sometimes irreversible, has been reported in patients receiving long-term or high doses. Advise patients to use caution when driving and operating machinery. Discontinue therapy immediately if any visual disturbances occur (eg, abnormality in visual acuity, visual field, color vision, or retinal macular areas [eg, pigmentary changes, loss of foveal reflex] or any visual symptoms [eg, light flashes and streaks]) that are not explained by difficulties of accommodation or corneal opacities. Observe patients after discontinuation; retinal changes and visual disturbances may progress after discontinuation of therapy. Retinal toxicity is primarily dose related; exceeding daily doses >6.5 mg/kg lean body weight greatly increases the risk; alternatively, some experts suggest that real body weight is a more accurate predictor of risk and daily doses of ≤5 mg/kg real body weight are recommended (Melles 2014). Risk may also be significantly increased with long-term use (>5 to 7 years) or a cumulative dose of 1,000 g (Marmor 2011). With long-term therapy, perform initial and periodic (every 3 month) ophthalmologic examinations, including visual acuity, expert slit-lamp, funduscopic, color vision, and visual field tests; increased frequency of examination is recommended in patients on daily doses >6.5 mg/kg lean body weight or cumulative dose >200 g; patients with renal impairment; elderly; and patients with impaired visual acuity. Refer to the American Academy of Ophthalmology recommendations for additional information (Marmor 2011). The Canadian labeling contraindicates use in patients with preexisting retinopathy.

• Visual changes: May impair accommodation and cause blurred vision; advise patients to use caution when driving and operating machinery.

Disease-related concerns:

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

• GI disorders: Use with caution in patients with GI disorders.

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

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

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

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

Special populations:

• Pediatric: Use caution due to increased sensitivity to aminoquinolones; long-term use in children is contraindicated. Canadian labeling contraindicates use in children <6 years of age or weighing <35 kg.

Concurrent drug therapy issues:

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

Other warnings/precautions:

• Appropriate use: Malaria: Hydroxychloroquine is not effective against chloroquine-resistant strains of P. falciparum.

• Appropriate use: Rheumatoid arthritis: Discontinue use if objective improvement (eg, reduced joint swelling, increased mobility) does not occur within 6 months. Safe use in treatment of juvenile arthritis has not been established.

• Experienced physician: [US Boxed Warning]: Should be prescribed by physicians familiar with its use.

Monitoring Parameters

CBC at baseline and periodically; liver function. Ophthalmologic exam at baseline and at least every 3 months during prolonged therapy (including visual acuity, slit-lamp, fundoscopic, and visual field exam); muscle strength (especially proximal, as a symptom of neuromyopathy) during long-term therapy

Pregnancy Considerations

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

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

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

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

Patient Education

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

• Patient may experience dizziness, headache, anxiety, lack of appetite, diarrhea, nausea, or abdominal cramps. Have patient report immediately to prescriber signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), vision changes, bruising, bleeding, unable to control body movements, twitching, difficulty swallowing, difficulty speaking, unable to control eye movements, seizures, mood changes, suicidal ideation, nightmares, hearing impairment, tinnitus, change in balance, chills, pharyngitis, muscle weakness, severe loss of strength and energy, or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).

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

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

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