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Irreversible maculopathy and macular degeneration have been reported with chloroquine or other 4-aminoquinoline compounds during postmarketing use. Irreversible retinopathy with retinal pigment changes (bull's eye appearance) and visual field defects (paracentral scotomas) have been reported in patients receiving long-term or high-dose 4-aminoquinoline therapy. Visual impairment (i.e., blurred vision and difficulty in focusing or accommodation), nyctalopia (night blindness), scotomatous vision with field defects of paracentral, pericentral ring types, and typically temporal scotomata (e.g., difficulty in reading with words tending to disappear, seeing half an object, misty vision, and fog before the eyes), and reversible corneal opacification (corneal deposits) have been reported. For patients with significant risk factors, monitoring should include annual examinations which include best corrected distance visual acuity (BCVA), automated threshold visual field (VF), and spectral domain optical coherence tomography (SD-OCT). For individuals without significant risk factors, annual exams can usually be deferred until 5 years of treatment. Discontinue chloroquine if ocular toxicity is suspected, and monitor the patient closely as retinal changes and visual disturbances may progress after cessation of therapy.[29758]

Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis, pleomorphic skin eruptions, skin and mucosal pigmentary changes (skin discoloration), lichen planus-like eruptions, pruritus, drug reaction with eosinophilia and systemic symptoms (DRESS), photosensitivity, hair loss (alopecia), bleaching of hair pigment (hair discoloration), urticaria, anaphylactoid reactions or anaphylactic shock, and angioedema have been reported during postmarketing use of chloroquine or other 4-aminoquinoline compounds. An acute attack of psoriasis can be precipitated by chloroquine in predisposed patients.[29758]

Chloroquine has been associated with acute generalized exanthematous pustulosis (AGEP). The non-follicular, pustular, erythematous rash starts suddenly and is associated with fever above 38 degrees C. Drugs are the main cause of AGEP. A period of 2 to 3 weeks after an inciting drug exposure appears necessary for a first episode of AGEP. Unintentional reexposure may cause a second episode within 2 days.[27736]

Hematological adverse reactions have been reported during postmarketing use of chloroquine or other 4-aminoquinoline compounds and include reversible agranulocytosis, aplastic anemia, pancytopenia, neutropenia, and thrombocytopenia. Chloroquine may cause hemolysis and hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency).[29758]

During postmarketing use, chloroquine and/or other 4-aminoquinoline compounds have been associated with sensorimotor disorders as well as skeletal muscle myopathy or neuromyopathy leading to progressive weakness (myasthenia) and atrophy of proximal muscle groups, depressed tendon reflexes (hyporeflexia), and abnormal nerve conduction. Periodically test knee and ankle reflexes to detect any evidence of muscular weakness. Discontinue chloroquine if weakness develops.[29758]

Nerve type deafness, tinnitus, and reduced hearing (hearing loss) in patients with preexisting auditory damage have been reported during postmarketing use of chloroquine or other 4-aminoquinoline compounds. Discontinue chloroquine with any hearing defects, and monitor the patient closely.[29758]

Cardiovascular adverse reactions associated with chloroquine or other 4-aminoquinoline compounds during postmarketing include cardiomyopathy (which may result in cardiac failure and in some cases fatal outcome), electrocardiogram (ECG) changes (particularly, inversion or flattening of the T-wave with widening of the QRS complex), and hypotension. Cardiac arrhythmias, conduction disorders such as bundle-branch block and AV block, QT prolongation, torsade de pointes (TdP), ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation) have been reported, including fatal cases. The risk is greater with higher doses, although cases have been reported with therapeutic doses. Chronic toxicity should be considered when conduction disorders, such as bundle-branch block or AV block, are diagnosed. Additionally, cases of cardiomyopathy resulting in cardiac failure with some cases of fatal outcome have been reported with chloroquine. Prompt discontinuation of chloroquine may prevent life-threatening complications if cardiotoxicity is suspected.[28225] [28229] [28230] [28231] [29758]

Adverse gastrointestinal effects noted with chloroquine or other 4-aminoquinoline compounds during postmarketing include hepatitis, elevated hepatic enzymes, nausea, vomiting, abdominal pain/cramps, diarrhea, and anorexia.[29758] Gastric effects can be minimized by taking chloroquine with food.[61673]

Nervous system adverse reactions associated with chloroquine or other 4-aminoquinoline compounds during postmarketing include headache (usually mild and transient), seizures, polyneuropathy, acute extrapyramidal symptoms (e.g., dystonia, dyskinesia, tongue protrusion, torticollis), and neuropsychiatric changes including psychosis, delirium, anxiety, agitation, insomnia, hallucinations, confusion, personality changes, depression, and suicidal ideation/behavior. Extrapyramidal symptoms usually resolve after treatment discontinuation and/or symptomatic treatment.[29758]

Chloroquine has been shown to cause severe hypoglycemia including loss of consciousness that could be life threatening in patients treated with or without antidiabetic medications. Monitor blood glucose and adjust treatment as necessary in patients presenting with clinical symptoms of hypoglycemia during chloroquine treatment.[29758]

Antimicrobial resistance to chloroquine therapy is widespread in P. falciparum and is reported in P. vivax. Prior to chloroquine use, it should be ascertained whether chloroquine is appropriate for use based on resistance patterns. Information regarding the geographic areas where resistance to chloroquine occurs is available from the Centers for Disease Control and Prevention.[29758]

Use of chloroquine for indications other than acute malaria is contraindicated in patients with ocular disease, specifically those who have retinal or visual field changes of any etiology. Irreversible retinal damage has been observed in some patients who received chloroquine. Significant risk factors for retinal damage include daily doses of chloroquine phosphate more than 2.3 mg/kg of actual body weight, duration of use more than 5 years, subnormal glomerular filtration (renal impairment or renal failure), use of some concomitant drug products such as tamoxifen, and concurrent macular disease. Baseline ophthalmological examination should be performed within the first year of starting chloroquine and should include best corrected distance visual acuity (BCVA), automated threshold visual field (VF) of the central 10 degrees (with retesting if an abnormality is noted), and spectral domain optical coherence tomography (SD-OCT). In Asian patients, retinal toxicity may first be noticed outside the macula, and VF testing should be performed in the central 24 degrees instead of the central 10 degrees. For patients with significant risk factors, monitoring should include annual examinations which include BCVA, VF, and SD-OCT. For individuals without significant risk factors, annual exams can usually be deferred until 5 years of treatment. Discontinue chloroquine if ocular toxicity is suspected, and monitor the patient closely as retinal changes and visual disturbances may progress after cessation of therapy.[29758] The use of chloroquine should be approached with caution in patients with Fabry disease, particularly those with ocular symptoms. The drug can cause a keratopathy that is clinically and ultrastructurally indistinguishable from keratopathy caused by Fabry disease; this drug-induced keratopathy is reversible with drug cessation. In addition, chloroquine poses a theoretical risk of decreased intracellular alpha-galactosidase A activity in Fabry disease patients. Chloroquine has been reported to induce clinical symptoms that mimic those of Fabry disease, including formation of inclusion bodies that are biochemically and ultrastructurally similar in most of the cells affected by Fabry disease (e.g., striated muscle, smooth muscle, etc.). The distinguishing factor is that the ultrastructural features of chloroquine toxicity in striated muscle, curvilinear bodies, are not present in renal cells.[30609]

Chloroquine is contraindicated in patients with known chloroquine hypersensitivity, or with a known allergy to 4-aminoquinolines. Patients with hydroxychloroquine hypersensitivity may have cross sensitivity to chloroquine.[29758]

QT prolongation, torsade de pointes (TdP), and ventricular arrhythmias have been reported with chloroquine use. The risk is greater with higher doses, although cases have been reported with therapeutic doses.[28225] [28229] [28230] [28231] [29758] Use chloroquine with caution in patients with conditions that may increase the risk of QT prolongation including congenital long QT syndrome, bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, geriatric patients, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation.[28432] [28457] [29758] [56592] [65180] In patients taking chloroquine with another drug that also prolongs the QT interval (see Therapeutic Drug Monitoring for recommendations specific to azithromycin with chloroquine used together for COVID-19), obtain a pre-treatment QTc using a standard 12-lead ECG, telemetry, or mobile ECG device. Obtain baseline electrolytes, including calcium, magnesium, and potassium. Determine if the patient is currently on any QT-prolonging medications that can be discontinued. Document high-risk cardiovascular and comorbid conditions. If the baseline QTc is 500 msec or more and/or the patient has an inherent tendency to develop an exaggerated QTc response (i.e., change of 60 msec or more), correct contributing electrolyte abnormalities, review and discontinue other unnecessary QTc prolonging medications, and proceed with close QTc surveillance. Obtain an initial on-therapy QTc approximately 2 to 4 hours after the first dose and then again at 48 and 96 hours after treatment initiation. If the baseline QTc is 460 to 499 msec (prepubertal), 470 to 499 msec (postpubertal males), or 480 to 499 msec (postpubertal females), correct contributing electrolyte abnormalities, review and discontinue other unnecessary QTc prolonging medications, and obtain an initial on-therapy QTc 48 and 96 hours after treatment initiation. If the baseline QTc is less than 460 msec (prepubertal), less than 470 msec (postpubertal males), or less than 480 msec (postpuberal females), correct electrolyte abnormalities and obtain an initial on-therapy QTc 48 and 96 hours after treatment initiation.[65170] Consider chronic chloroquine toxicity when conduction disorders, such as bundle-branch block or AV block, are diagnosed. Cases of cardiomyopathy resulting in cardiac failure, sometimes fatal, have been reported with chloroquine. Prompt discontinuation of chloroquine may prevent life-threatening complications if cardiotoxicity is suspected.[29758]

Chloroquine should not be used in patients with psoriasis unless the benefit to the patient outweighs the potential risks because it may precipitate a severe attack of psoriasis.[29758]

Chloroquine should be used with caution in patients with hepatic disease or alcoholism because the drug is metabolized in the liver and accumulation can occur producing toxic effects. Patients receiving other hepatotoxic drugs also should be treated with caution.[29758]

Chloroquine should be used with caution in patients with neurological disease including preexisting hearing impairment or seizure disorder. Polyneuritis, ototoxicity, seizures, neuromyopathy, and acute extrapyramidal symptoms (dystonia, dyskinesia, tongue protrusion, torticollis) have occurred with chloroquine therapy. Symptoms of muscle weakness and response of knee and ankle reflexes should be investigated regularly. If muscle weakness, extrapyramidal symptoms, or any defects in hearing occur during chloroquine therapy, the drug should be discontinued immediately and the patient observed closely.[29758]

Chloroquine can exacerbate porphyria or may cause hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency). Use chloroquine with caution in patients with these conditions. Blood monitoring for hemolytic anemia in G6PD deficiency patients may be necessary, particularly with concomitant use of other medications associated with hemolysis.[29758]

Use chloroquine with caution in patients with hypoglycemia or diabetes mellitus. Chloroquine can cause severe, life-threatening hypoglycemia in patients with or without antidiabetic medications. Warn patients about the risk of hypoglycemia and the associated clinical signs and symptoms. Monitor blood glucose and adjust treatment as necessary in patients presenting with clinical symptoms of hypoglycemia during chloroquine treatment.[29758]

Children are especially sensitive to the 4-aminoquinoline compounds. Fatalities have been reported after accidental exposure of chloroquine; some cases involved relatively small doses (e.g., 0.75 g or 1 g in a 3-year-old child). Strongly warn patients to keep chloroquine out of the reach of pediatric patients, including neonates, infants, children, and adolescents.[29758]

Weigh the benefit of chloroquine prophylaxis or treatment of malaria against the potential risk to the fetus, and consider the drug's potential to remain in the body for several months after discontinuation of therapy.[29758] [63990] [64059] In humans at recommended doses for prophylaxis and treatment of malaria, observational studies as well as a meta-analysis, including a small number of prospective studies with chloroquine during pregnancy, have shown no increase in the rate of birth defects or spontaneous abortions.[29758] Guidelines recommend chloroquine as a treatment option for acute malaria and for prophylaxis in pregnant women during all trimesters. Chloroquine crosses the placenta, but the potential damage to the mother from malaria is greater than the drug's risk to the fetus. Weekly prophylactic doses appear to have minimal adverse effects when administered during pregnancy.[63990] [64059] Animal studies showed embryo-fetal developmental toxicity at doses 3 to 16 times the maximum recommended therapeutic dose and the potential of genotoxicity in some test systems. Autoradiographic studies have shown accumulation in the eyes and ears when chloroquine is administered at the start or end of gestation in animal studies.[29758]

Use caution when administering chloroquine to breast-feeding women. Chloroquine is excreted into breast milk. The excretion of chloroquine and the major metabolite, desethylchloroquine, in breast milk was investigated in 11 lactating mothers following a single oral dose of chloroquine (600 mg base).The maximum daily dose of the drug that the infant received from breast-feeding was about 0.7% of the maternal start dose of the drug in malaria chemotherapy. Separate chemoprophylaxis for an infant is required.[29758] However, previous American Academy of Pediatrics (AAP) recommendations consider chloroquine usually compatible with breast-feeding, and chloroquine has an established dosage in infants.[27500]

Chloroquine should be used with caution in males because animal studies suggest that infertility is possible; after 30 days of oral treatment, testosterone levels and weight of testes, epididymis, seminal vesicles, and prostate decreased.[29758]