Hydroxychloroquine can cause ocular toxicity including irreversible retinal damage related to cumulative dose and treatment duration. A baseline ocular exam should be performed within the first year of hydroxychloroquine treatment. This baseline exam should include best corrected distance visual acuity (BCVA), an automated threshold visual field (VF) of the central 10 degrees (with retesting if an abnormality is noted), and spectral domain ocular coherence tomography (SD-OCT). Annual exams are recommended for patients at higher risk of retinal damage. For patients without significant risk factors, annual exams may be deferred until 5 years of treatment. In Asian patients, retinal toxicity may first be noticed outside the macula; therefore, visual field testing should be performed in the central 24 degrees instead of the central 10 degrees. Discontinue hydroxychloroquine if ocular toxicity is suspected and monitor the patient closely for ocular disease (i.e., retinal changes) and visual disturbance which may progress even after discontinuation of therapy. Other ocular adverse events include retinopathy, retinal pigment changes (bull's eye appearance), visual field defects/visual impairment (paracentral scotomata), macular degeneration, decreased dark adaptation, corneal edema, and corneal opacification.[41806]

Serious skin reaction have been reported with the use of hydroxychloroquine and include Stevens-Johnson syndrome, and toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), photosensitivity, and acute generalized exanthematous pustulosis (AGEP). Monitor for serious skin reactions, especially in patients receiving a drug that may also induce dermatitis. Patients should seek medical attention if they experience signs and symptoms of serious skin reactions, including blisters on the skin, eyes, lips, or inside the mouth; itching or burning; with or without fever. Other allergic or dermatologic reactions include Other allergic and dermatologic reactions have been reported with the use of hydroxychloroquine. These include alopecia, hair color changes (hair discoloration), rash, pruritus, photosensitivity, hyperpigmentation (skin discoloration), exfoliative dermatitis, erythema multiforme, urticaria, angioedema, and bronchospasm.[41806]

Hydroxychloroquine may precipitate a severe attack of psoriasis that may be associated with pyrexia and hyperleukocytosis. Monitor patients with known psoriasis for a flare-up of the psoriasis.[41806]

Skeletal muscle myopathy or peripheral neuropathy leading to progressive weakness and atrophy of proximal muscle groups, depression of tendon reflexes, and abnormal nerve conduction has been reported. Muscle and nerve biopsies have been associated with curvilinear bodies and muscle fiber atrophy with vacuolar changes. Muscle and nerve biopsies have showed associated phospholipidosis. Drug-induced phospholipidosis may occur in other organ systems. Assess muscle strength and deep tendon reflexes periodically in patients on long-term therapy with hydroxychloroquine. If muscle or nerve toxicity is suspected or demonstrated by tissue biopsy, discontinue hydroxychloroquine therapy.[41806]

Hematological adverse reactions of hydroxychloroquine include myelosuppression (bone marrow suppression), including anemia, aplastic anemia, agranulocytosis, leukopenia, and thrombocytopenia. Hemolysis/hemolytic anemia has been reported in individuals with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency. Monitor blood cell counts periodically if patients are given prolonged hydroxychloroquine therapy. If myelosuppression develops which is not attributable to the disease under treatment occurs, discontinue hydroxychloroquine.[41806]

Sensorineural hearing loss and tinnitus have been reported with hydroxychloroquine or other 4-aminoquinolines.[41806]

Fatal and life-threatening cases of cardiotoxicity, including cardiomyopathy, have been reported in patients treated with hydroxychloroquine. Signs and symptoms of cardiac compromise have occurred during acute and chronic treatment with the drug. Patients may present with ventricular hypertrophy, pulmonary hypertension, and conduction disorders including sick sinus syndrome. ECG findings include AV block or right or left bundle-branch block. In multiple cases, endomyocardial biopsy revealed an association of cardiomyopathy with phospholipidosis in absence of inflammation, infiltration, or necrosis. Drug-induced phospholipidosis may occur with other organs. Chronic toxicity should be considered when conduction disorders or biventricular hypertrophy are diagnosed. If cardiotoxicity is suspected or demonstrated by tissue biopsy, prompt discontinuation of hydroxychloroquine may prevent life-threatening cardiac complications. Additionally, hydroxychloroquine causes QT prolongation. The magnitude of QT prolongation may increase with increasing drug concentrations. Ventricular arrhythmias (i.e., ventricular fibrillation, ventricular tachycardia) and torsade de pointes have been reported in patients taking hydroxychloroquine. Monitor the ECG and cardiac function as indicated during hydroxychloroquine therapy. Cardiac disorders reported with the class of 4-aminoquinoline drugs postmarketing have included cardiomyopathy, heart failure, QT-interval prolongation, ventricular tachycardia, torsade de pointes, AV block, bundle-branch block, sick sinus syndrome, and pulmonary hypertension.[41806]

Adverse gastrointestinal (GI) effects reported with hydroxychloroquine or other 4-aminoquinolines include nausea, vomiting, abdominal pain, diarrhea, and anorexia. These effects are associated with oral administration and can be minimized by taking hydroxychloroquine with food. Abnormal liver function tests and fulminant hepatic failure have also been reported.[41806]

Suicidal behavior, suicidal ideation, and other neuropsychiatric adverse events have been reported in patients treated with hydroxychlorquine. Neuropsychiatric adverse events typically occur within the first month after starting hydroxychloroquine and have been reported in patients with and without prior history of psychiatric disorders. Psychiatric and CNS adverse events reported with hydroxychloroquine or other 4-aminoquinolines include headache, dizziness, affect/emotional lability, irritability, psychosis, nervousness, depression, hallucinations, anxiety, agitation, confusion, delusions, paranoia, mania, sleep disorders (insomnia, night terrors, nightmares), vertigo, nystagmus, ataxia, seizures, and extrapyramidal disorders such as dystonic reaction, dyskinesia, and tremor. Assess the risk and benefit of continued treatment in patients who develop neuropsychiatric reactions, including new or worsening depression, suicidal thoughts or behavior, or mood changes. Given the long half-life of the drug, it may take several weeks for the symptoms to partially or fully abate after stopping hydroxychlorquine.[41806]

Weight loss and fatigue have been reported with the use of hydroxychloroquine or other 4-aminoquinolines.[41806]

Hydroxychloroquine 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 hydroxychloroquine treatment.[41806]

Hydroxychloroquine may cause nephrotoxicity. Cases of proteinuria with or without a moderate reduction in glomerular filtration rate have been reported with hydroxychloroquine therapy. Renal biopsy revealed phospholipidosis without immune deposits, inflammation, and/or increased cellularity. Phospholipidosis may be considered as a potential cause of renal injury in patients receiving hydroxychloroquine with underlying connective tissue disorders. Drug-induced phospholipidosis may occur in other organ systems. If renal toxicity is suspected or demonstrated by tissue biopsy, discontinue hydroxychloroquine.[41806] [68436]

Use of hydroxychloroquine in patients with porphyria has been shown to exacerbate porphyria. Additionally, in patients with porphyria cutanea tarda (PCT), cases of hepatotoxicity have developed following administration of hydroxychloroquine at doses ranging from 200 mg twice weekly to 400 mg daily. For most PCT-related cases, patients presented with markedly elevated hepatic enzymes (greater than 20-times upper limit of normal) within days to months of starting hydroxychloroquine. If a patient is found to have an abnormal liver function test (e.g., ALT greater than 3-times ULN, total bilirubin greater than 2-times ULN), interrupt treatment with hydroxychloroquine and investigate for the probable cause.[41806] [68584]

Fatal and life-threatening cases of cardiotoxicity, including cardiomyopathy, have been reported in patients treated with hydroxychloroquine. Signs and symptoms of cardiac compromise have occurred with acute and chronic hydroxychloroquine therapy. In multiple cases, endomyocardial biopsy revealed an association of cardiomyopathy with phospholipidosis in absence of inflammation, infiltration, or necrosis. Drug-induced phospholipidosis may occur in other organs. Consider chronic toxicity when conduction disorders (bundle-branch block, AV block) or biventricular hypertrophy are diagnosed. If cardiotoxicity is suspected or demonstrated by tissue biopsy, prompt discontinuation of hydroxychloroquine may prevent life-threatening cardiac complications.[41806] Hydroxychloroquine has caused fatal and life-threatening cases of ventricular arrhythmias. Hydroxychloroquine prolongs the QT interval; the magnitude of QT prolongation may increase with increasing drug concentrations. Avoid hydroxychloroquine in patients with conditions that may increase the risk of QT prolongation including congenital long QT syndrome, proarrhythmic conditions (e.g. bradycardia), AV block, cardiac disease, heart failure, stress-related cardiomyopathy, myocardial infarction, history of ventricular arrhythmias, 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] [41806] [56592] [65180]

Severe and irreversible retinal toxicity has been reported with the use of hydroxychloroquine and ocular toxicity is related to cumulative dosage and treatment duration. Risk factors for retinal damage include daily doses more than 6.5 mg/kg (5 mg/kg base) of actual body weight, duration of use greater than 5 years, renal dysfunction, use of concomitant drugs such as tamoxifen, and concurrent macular ocular disease. A baseline ocular exam should be performed within the first year of hydroxychloroquine treatment. This baseline exam should include best corrected distance visual acuity (BCVA), an automated threshold visual field (VF) of the central 10 degrees (with retesting if an abnormality is noted), and spectral domain ocular coherence tomography (SD-OCT). Annual exams, which include BCVA, VF, and SD-OCT, are recommended for patients at higher risk of retinal damage. For patients without significant risk factors, annual ocular exams may be deferred until 5 years of treatment. In Asian patients, retinal toxicity may first be noticed outside the macula; therefore, visual field testing should be performed in the central 24 degrees instead of the central 10 degrees. Discontinue hydroxychloroquine if ocular toxicity is suspected and monitor the patient closely for retinal changes and visual disturbance which may progress even after discontinuation of therapy.[41806]

Hydroxychloroquine is contraindicated in patients with known hypersensitivity to 4-aminoquinoline compounds.[41806] Serious adverse reactions have been reported with the use of hydroxychloroquine including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), acute generalized exanthematous pustulosis (AGEP). Monitor for serious skin reactions, especially in patients receiving a drug that may also induce dermatitis. Advise patients to seek medical attention promptly if they experience signs and symptoms of serious rash or skin reactions such as blisters on the skin, eyes, lips or in the mouth, itching or burning, with or without fever. Discontinue hydroxychloroquine if these severe reactions occur.[41806]

Avoid use of hydroxychloroquine in patients with psoriasis unless the benefit to the patients outweighs the possible risk. Hydroxychloroquine has been shown to precipitate severe flare-ups of psoriasis.[41806]

Avoid use of hydroxychloroquine in patients with porphyria, as treatment has been shown to exacerbate porphyria. Additionally, the safe and effective use of hydroxychloroquine for the treatment of porphyria cutanea tarda (PCT) has not been established; the drug is not approved for this indication. In patients with PCT, cases of hepatotoxicity have developed following administration of hydroxychloroquine at doses ranging from 200 mg twice weekly to 400 mg daily. For most PCT-related cases, patients presented with marked elevations in transaminases (greater than 20-times upper limit of normal) within days to months of starting hydroxychloroquine. In some cases, the diagnosis of PCT was not made until after hydroxychloroquine-induced liver injury occurred. Some cases were associated with other risk factors for hepatic injury (e.g., alcohol use, concomitant hepatotoxic medications). Promptly measure liver function tests in patients who report symptoms that may indicate hepatic injury (e.g., fatigue, rash, nausea, dark urine, jaundice). If a patient is found to have an abnormal liver function test (e.g., ALT greater than 3-times ULN, total bilirubin greater than 2-times ULN), interrupt treatment with hydroxychloroquine and investigate for the probable cause.[41806] [68584]

Hydroxychloroquine may cause bone marrow suppression including aplastic anemia, agranulocytosis, leukopenia, or thrombocytopenia. Monitor blood cell counts periodically in patients on prolonged therapy. If a treated patient develops myelosuppression that cannot be attributable to the disease, discontinue the drug. Administer hydroxychloroquine with caution in patients with glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency) due to the risk of hemolysis. Monitor for hemolytic anemia, especially in patients taking other drugs associated with hemolysis.[41806]

Hydroxychloroquine should be used with caution in patients with neurological disease, peripheral neuropathy, or myopathy. Skeletal muscle myopathy or peripheral neuropathy leading to progressive weakness and atrophy of proximal muscle groups, depressed tendon reflexes, and abnormal nerve conduction have been reported. Muscle and nerve biopsies have shown associated phospholipidosis. Drug-induced phospholipidosis may occur in other organ systems. Assess muscle strength and deep tendon reflexes periodically in patients on long-term therapy with hydroxychloroquine. Advise patients to report any symptoms of muscle weakness. If muscle or nerve toxicity is suspected or demonstrated by tissue biopsy, discontinue hydroxychloroquine therapy.[41806]

Suicidal behavior, suicidal ideation, and other neuropsychiatric events have been reported in patients treated with hydroxychlorquine. A neuro-psychiatric event will typically occur within the first month after starting hydroxychloroquine and these events have been reported in patients with and without prior history of psychiatric disorders. Alert patients to contact their healthcare provider if they experience new or worsening depression, suicidal ideation or thoughts, or mood or behavioral changes. Asses the risk and benefit of continued treatment with hydroxychlorquine for patients who develop these symptoms. Given the long half-life of the drug, it may take several weeks for the symptoms to partially or fully abate.[41806]

Use hydroxychloroquine with caution in patients with hypoglycemia or diabetes mellitus. Hydroxychloroquine can cause severe, life-threatening hypoglycemia in patients treated 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 hydroxychloroquine treatment.[41806]

A reduction in the dosage of hydroxychloroquine may be necessary in patients with renal disease, including renal impairment or renal failure. Additionally, renal impairment is a risk factor for retinal damage due to hydroxychloroquine, which is related to cumulative dosage and treatment duration. Hydroxychloroquine has also been associated with nephrotoxicity. Cases of proteinuria with or without a moderate reduction in glomerular filtration rate have been reported with hydroxychloroquine therapy. Renal biopsy revealed phospholipidosis without immune deposits, inflammation, and/or increased cellularity. Phospholipidosis may be considered as a potential cause of renal injury in patients receiving hydroxychloroquine with underlying connective tissue disorders. Drug-induced phospholipidosis may occur in other organ systems. If renal toxicity is suspected or demonstrated by tissue biopsy, discontinue hydroxychloroquine.[41806]

Hydroxychloroquine should be used with caution in patients with hepatic disease. A dose reduction may be necessary.[41806]

Prolonged clinical experience over decades of use and available data from published epidemiologic and clinical studies with hydroxychloroquine use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Hydroxychloroquine readily crosses the placenta with cord blood levels corresponding to maternal plasma levels. No retinal toxicity, ototoxicity, cardiotoxicity, or growth and developmental abnormalities have been observed in children who were exposed to hydroxychloroquine in utero. Available epidemiologic and clinical studies have methodological limitations including small sample size and study design. There are risks to the mother and fetus associated with untreated or increased maternal disease activity from malaria, rheumatoid arthritis, and systemic lupus erythematosus (SLE) during pregnancy that should be considered. There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to hydroxychloroquine during pregnancy. Encourage patients to register by contacting 1-877-311-8972.[41806] Hydroxychloroquine is considered to be compatible for use during pregnancy in some anti-rheumatic guidelines, and may be continued in pregnancy for maintenance of remission or treatment of a disease flare.[62180] [64661] [64662] Hydroxychloroquine may also be appropriate for pregnancies complicated by lupus.[34349] [34358] Guidelines also recommend hydroxychloroquine as an alternative to chloroquine as a treatment option for acute malaria and for prophylaxis in pregnant women during all trimesters.[68402] [68403] Animal reproductive studies have not been conducted.[41806]

Data regarding the use of hydroxychloroquine during breast-feeding report that hydroxychloroquine is present in human milk at low levels. No adverse reactions have been reported in breastfed infants. No retinal toxicity, ototoxicity, cardiotoxicity, or growth and developmental abnormalities have been observed in children who were exposed to hydroxychloroquine through breastmilk. There is no information on the effect of hydroxychloroquine on milk production.[41806] Hydroxychloroquine is considered to be compatible for use during breast-feeding in some anti-rheumatic guidelines, and may be continued during lactation for maintenance of remission or treatment of a disease flare.[62180] [64661] [64662] During lactation studies, breast milk concentrations ranged from 10.6 to 1,392 mcg/L  and breast-fed infants would likely receive 0.2 mg/kg or less of hydroxychloroquine.[48476] [48477] [48478] [48479] In infants monitored for up to at least 1 year of age, careful follow-up found no adverse effects on growth, vision, or hearing.[48474] [48475] The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for the medication and any potential adverse effects on the breastfed child from hydroxychloroquine exposure or from the underlying maternal condition.[41806]