[Mead]

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Adverse Reactions
1% to 10%: Ophthalmic: Retinopathy (4%; serum concentration dependent [Petri 2019]; early changes reversible [may progress despite discontinuation if advanced])

Frequency not defined:

Dermatologic: Acute generalized exanthematous pustulosis, alopecia, bullous rash, dyschromia (skin and mucosal), erythema multiforme, exacerbation of psoriasis, exfoliative dermatitis, hair discoloration, pruritus, skin photosensitivity, skin rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria

Endocrine & metabolic: Exacerbation of porphyria, severe hypoglycemia, weight loss

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

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

Hepatic: Abnormal hepatic function tests, acute hepatic failure

Hypersensitivity: Angioedema

Immunologic: Drug reaction with eosinophilia and systemic symptoms

Nervous system: Ataxia, dizziness, emotional lability, fatigue, headache, irritability, nervousness, nightmares, psychosis, seizure, sensorineural hearing loss, suicidal tendencies, vertigo

Neuromuscular & skeletal: Myopathy (including palsy 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)

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, prolonged QT interval on ECG, torsades de pointes, ventricular arrhythmia, ventricular tachycardia (FDA Safety Alert, April 24, 2020)

Endocrine & metabolic: Hypoglycemia (can be severe; 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: Agitation (FDA Safety Alert, April 1, 2020), confusion (FDA Safety Alert, April 1, 2020), delirium (FDA Safety Alert, April 1, 2020), extrapyramidal reaction (FDA Safety Alert, April 1, 2020), hallucination (FDA Safety Alert, April 1, 2020)

Ophthalmic: Epithelial keratopathy (Dosso 2007)

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

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
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; Glader 2017; Luzzatto 2016; Youngster 2010). Safety in Class I G6PD deficiency (ie, severe form of the deficiency associated with chronic hemolytic anemia) is generally unknown (Glader 2017). 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.

• 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. Safety and efficacy have not been established for chronic use in children for juvenile idiopathic arthritis or for systemic lupus erythematosus.

Concurrent drug therapy issues:

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