HYDROXYCHLOROQUINE: 66,691 Adverse Event Reports & Safety Profile

Hydroxychloroquine sulfate is a white or practically white, crystalline powder, freely soluble in water; practically insoluble in alcohol, chloroform, and in ether. The chemical name for hydroxychloroquine sulfate is 2-[[4-[(7-Chloro-4-quinolyl)amino]pentyl]ethylamino] ethanol sulfate (1:1). Its structural formula is The molecular weight of hydroxychloroquine sulfate is 433.95, and molecular formula is C 18 H 26 CIN 3 O•H 2 SO 4 .

Hydroxychloroquine Sulfate

Tablets, USP contains 100 mg hydroxychloroquine sulfate, equivalent to 77.5 mg base, and are for oral administration.

Inactive

Ingredients: corn starch, crospovidone, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, polyethylene glycol, polyvinyl alcohol, talc and titanium dioxide.

Hydroxychloroquine Sulfate

Tablets, USP contain 200 mg hydroxychloroquine sulfate, equivalent to 155 mg base, and are for oral administration.

Inactive

Ingredients: corn starch, crospovidone, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, polyethylene glycol, polyvinyl alcohol, talc and titanium dioxide.

Hydroxychloroquine Sulfate

Tablets, USP contains 300 mg hydroxychloroquine sulfate, equivalent to 232.5 mg base, and are for oral administration.

Inactive

Ingredients: corn starch, crospovidone, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide and yellow iron oxide.

Hydroxychloroquine Sulfate

Tablets, USP contain 400 mg hydroxychloroquine sulfate, equivalent to 310 mg base, and are for oral administration.

Inactive

Ingredients: corn starch, crospovidone, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, polyethylene glycol, polyvinyl alcohol, talc and titanium dioxide. Meets USP Dissolution Test 1 Chemical Structure

AND USAGE Hydroxychloroquine sulfate tablets are an antimalarial and antirheumatic indicated for the:

• Treatment of uncomplicated malaria due to Plasmodium falciparum, Plasmodium malariae, Plasmodium ovale , and Plasmodium vivax in adult and pediatric patients. ( 1.1 )
• Prophylaxis of malaria in geographic areas where chloroquine resistance is not reported in adult and pediatric patients. ( 1.1 )
• Treatment of rheumatoid arthritis in adults. ( 1.2 )
• Treatment of systemic lupus erythematosus in adults. ( 1.3 )
• Treatment of chronic discoid lupus erythematosus in adults. ( 1.4 ) Limitations of Use ( 1.1 ): Hydroxychloroquine sulfate tablets are not recommended for the:
• Treatment of complicated malaria.
• Treatment of chloroquine or hydroxychloroquine-resistant strains of Plasmodium species.
• Treatment of malaria acquired in geographic areas where chloroquine resistance occurs or when the Plasmodium species has not been identified.
• Prophylaxis of malaria in geographic areas where chloroquine resistance occurs.
• Prevention of relapses of P. vivax or P. ovale because it is not active against the hypnozoite liver stage forms of these parasites. For radical cure of P. vivax and P. ovale infections, concomitant therapy with an 8-aminoquinoline drug is necessary.

1.1 Malaria Hydroxychloroquine sulfate tablets are indicated in adult and pediatric patients for the:

• Treatment of uncomplicated malaria due to Plasmodium falciparum, Plasmodium malariae, Plasmodium vivax , and Plasmodium ovale .
• Prophylaxis of malaria in geographic areas where chloroquine resistance is not reported. Limitations of Use: Hydroxychloroquine sulfate tablets are not recommended for:
• Treatment of complicated malaria.
• Treatment of malaria by chloroquine or hydroxychloroquine-resistant strains of Plasmodium species [see Microbiology (12.4) ].
• Treatment of malaria acquired in geographic areas where chloroquine resistance occurs or when the Plasmodium species has not been identified.
• Prophylaxis of malaria in geographic areas where chloroquine resistance occurs.
• Prevention of relapses of P. vivax or P. ovale because it is not active against the hypnozoite liver stage forms of these parasites. For radical cure of P. vivax and P. ovale infections, concomitant therapy with an 8-aminoquinoline drug is necessary [see Microbiology (12.4) ]. For the most current information about drug resistance, refer to the latest recommendations from the Center for Disease Control and Prevention 1 .

1.2 Rheumatoid Arthritis Hydroxychloroquine sulfate tablets are indicated for the treatment of acute and chronic rheumatoid arthritis in adults.

1.3 Systemic Lupus Erythematosus Hydroxychloroquine sulfate tablets are indicated for the treatment of systemic lupus erythematosus in adults.

1.4 Chronic Discoid Lupus Erythematosus Hydroxychloroquine sulfate tablets are indicated for the treatment of chronic discoid lupus erythematosus in adults.

AND ADMINISTRATION Malaria in Adult and Pediatric Patients ( 2.2 ):

• Prophylaxis: Begin weekly doses 2 weeks prior to travel to the endemic area, continue weekly doses while in the endemic area, and continue the weekly doses for 4 weeks after leaving the endemic area: - Adults: 400 mg once a week - Pediatric patients ≥ 31 kg: 6.5 mg/kg up to 400 mg, once a week
• Treatment of Uncomplicated Malaria: See Full Prescribing Information (FPI) for complete dosing information.

Rheumatoid

Arthritis in Adults ( 2.3 ):

• Initial dosage: 400 mg to 600 mg daily
• Chronic dosage: 200 mg once daily or 400 mg once daily (or in two divided doses)

Systemic Lupus

Erythematosus in Adults ( 2.4 ):

• 200 mg once daily or 400 mg once daily (or in two divided doses)

Chronic Discoid Lupus

Erythematosus in Adults ( 2.5 ):

• 200 mg once daily or 400 mg once daily (or in two divided doses)

2.1 Important Administration Instructions Administer hydroxychloroquine sulfate tablets orally with food or milk. Do not crush or divide the tablets.

2.2 Dosage for Malaria in Adult and Pediatric Patients Hydroxychloroquine sulfate tablets are not recommended in pediatric patients less than 31 kg because the lowest available strength (200 mg) exceeds the recommended dose for these patients and it cannot be divided.

Prophylaxis

Treatment must start 2 weeks before travel to an endemic area. Advise the patient to take the prophylaxis dosage once a week, staring 2 weeks prior to travel to the endemic area, on the same day every week, continuing the same weekly dose while in the endemic area, and for 4 weeks after leaving the endemic area. The recommended prophylaxis dosage is:

• Adult patients: 400 mg once a week
• Pediatric patients ≥ 31kg: 6.5 mg/kg actual body weight (up to 400 mg) once a week Treatment of Uncomplicated Malaria The dosages for the treatment of uncomplicated malaria are:
• Adult patients: Administer 800 mg initially; subsequently administer 400 mg at 6 hours, 24 hours, and 48 hours after the initial dose (total dosage = 2,000 mg).
• Pediatric patients ≥ 31 kg: Administer 13 mg/kg (up to 800 mg) initially; subsequently administer 6.5 mg/kg (up to 400 mg) at 6 hours, 24 hours, and 48 hours after the initial dose (total dosage = 31 mg/kg - up to 2,000 mg). For radical cure of P. vivax and P. ovale infections, concomitant therapy with an 8­-aminoquinoline drug is necessary [see Microbiology (12.4) ].

2.3 Dosage for Rheumatoid Arthritis in Adults The recommended dosage is:

• Initial dosage: 400 mg to 600 mg daily as a single daily dose or two divided doses. The action of hydroxychloroquine is cumulative and may require weeks to months for maximum therapeutic effect. Daily doses exceeding 5 mg/kg (actual weight) of hydroxychloroquine sulfate increase the incidence of retinopathy [see Warnings and Precautions (5.2) ].
• Chronic dosage: 200 mg once daily to 400 mg daily, as a single dose or two divided doses. Corticosteroids, salicylates, and other antirheumatic agents may be used concomitantly with hydroxychloroquine sulfate tablets.

2.4 Dosage for Systemic Lupus Erythematosus in Adults The recommended dosage is 200 mg given once daily, or 400 mg given once daily or in two divided doses.

2.5 Dosage for Chronic Discoid Lupus Erythematosus in Adults The recommended dosage is 200 mg given once daily, or 400 mg given once daily or in two divided doses.

Hydroxychloroquine sulfate tablets are contraindicated in patients with known hypersensitivity to 4-aminoquinoline compounds.

• Patients with hypersensitivity to 4-aminoquinoline compounds ( 4 )

REACTIONS The following adverse reactions are described in greater detail in other sections:

• Cardiomyopathy and Ventricular Arrhythmias [see Warnings and Precautions ( 5.1 )]
• Retinal Toxicity [see Warnings and Precautions ( 5.2 )]
• Serious Skin Reactions [see Warnings and Precautions ( 5.3 )]
• Worsening of Psoriasis [ see Warnings and Precautions ( 5.4 )]
• Risks Associated with Use in Porphyria [see Warnings and Precautions ( 5.5 )]
• Hematologic Toxicity [see Warnings and Precautions ( 5.6 )]
• Hemolytic Anemia Associated with G6PD [see Warnings and Precautions ( 5.7 )]
• Skeletal Muscle Myopathy or Neuropathy [see Warnings and Precautions ( 5.8 )]
• Neuropsychiatric Reactions Including Suicidality [see Warnings and Precautions ( 5.9 )]
• Hypoglycemia [see Warnings and Precautions ( 5.10 )]
• Renal Toxicity [see Warnings and Precautions ( 5.11 )] The following adverse reactions have been identified during post-approval use of 4- aminoquinoline drugs, including hydroxychloroquine sulfate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: - Blood and lymphatic system disorders : Bone marrow depression, anemia, aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia - Cardiac disorders: Cardiomyopathy, cardiac failure, QT-interval prolongation, ventricular tachycardia, torsades de pointes, atrioventricular block, bundle branch block, sick sinus syndrome, pulmonary hypertension - Ear and labyrinth disorders : Vertigo, tinnitus, nystagmus, sensorineural hearing loss - Eye disorders : Retinopathy, retinal pigmentation changes (typically bull's eye appearance), visual field defects (paracentral scotomas), macular degeneration, corneal edema, corneal opacities, decreased dark adaptation - Gastrointestinal disorders : Nausea, vomiting, diarrhea, abdominal pain - General disorders : Fatigue - Hepatobiliary disorders : Abnormal liver function tests, fulminant hepatic failure - Immune system disorders : Urticaria, angioedema, bronchospasm - Metabolism and nutrition disorders : Anorexia, hypoglycemia, weight loss - Musculoskeletal and connective tissue disorders : Proximal myopathy, depressed tendon reflexes, abnormal nerve conduction - Nervous system disorders : Ataxia, dizziness, headache, seizure, extrapyramidal disorders (dystonia, dyskinesia, tremor) - Neuropsychiatric disorders: Affect/emotional lability, irritability, nervousness, psychosis, suicidal ideation, suicidal behavior, depression, hallucinations, anxiety, agitation, confusion, delusions, paranoia, mania and sleep disorders (insomnia, night terrors, nightmares) - Skin and subcutaneous tissue disorders : Alopecia, hair color changes, rash, pruritus, photosensitivity, psoriasis exacerbation, hyperpigmentation, exfoliative dermatitis, erythema multiforme, acute generalized exanthematous pustulosis, Drug Rash with Eosinophilia and Systemic Symptoms (DRESS syndrome), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) The most common adverse reactions reported are: nausea, vomiting, diarrhea, and abdominal pain. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

AND PRECAUTIONS

• Cardiomyopathy and Ventricular Arrhythmias : Fatal or life-threatening cardiomyopathy and ventricular arrhythmias were reported. (5.1)
• Retinal Toxicity : Irreversible retinal damage is related to cumulative dosage and treatment duration. Baseline retinal exam and exams during treatment are recommended. (5.2)
• Serious Skin Reactions : Stevens Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, acute generalized exanthematous pustulosis have been reported. (5.3)
• Worsening of Psoriasis : Avoid in patients with psoriasis. (5.4)
• Risks Associated with Use in Porphyria : Avoid in patients with porphyria. Hepatotoxicity was reported in patients with porphyria cutanea tarda. (5.5)
• Hematologic Toxicity : Discontinue if myelosuppression occurs. (5.6)
• Renal Toxicity : Consider phospholipidosis as a possible cause of renal injury in patients with underlying connective tissue disorders. Discontinue hydroxychloroquine sulfate if renal toxicity is suspected or demonstrated by tissue biopsy in any organ system. (5.1, 5.8, 5.11)

5.1 Cardiomyopathy and Ventricular Arrhythmias Fatal and life-threatening cases of cardiotoxicity, including cardiomyopathy, have been reported in patients treated with hydroxychloroquine sulfate tablets. Signs and symptoms of cardiac compromise have occurred during acute and chronic hydroxychloroquine sulfate tablets treatment. In multiple cases, endomyocardial biopsy showed association of the cardiomyopathy with phospholipidosis in the absence of inflammation, infiltration, or necrosis. Drug-induced phospholipidosis may occur in other organ systems <span class="opacity-50 text-xs">[see Warnings and Precautions (5.8 , 5.11 ) ]</span>. Patients may present with ventricular hypertrophy, pulmonary hypertension and conduction disorders including sick sinus syndrome. ECG findings include atrioventricular, right or left bundle branch block. Hydroxychloroquine sulfate tablets has a potential to prolong the QT interval. Ventricular arrhythmias (including torsades de pointes) have been reported in hydroxychloroquine sulfate tablets-treated patients. The magnitude of QT prolongation may increase with increasing concentrations of the drug. Therefore, the recommended dose should not be exceeded [ see Adverse Reactions (6) , Overdosage (10) ] . Avoid hydroxychloroquine sulfate tablets administration in patients with congenital or documented acquired QT prolongation and/or known risk factors for prolongation of the QT interval such as:

• Cardiac disease, e.g., heart failure, myocardial infarction.
• Proarrhythmic conditions, e.g., bradycardia (< 50 bpm).
• History of ventricular dysrhythmias.
• Uncorrected hypokalemia and/or hypomagnesemia.
• Concomitant administration with QT interval prolonging agentsas this may lead to an increased risk for ventricular arrhythmias. [ see Drug Interactions (7.1) ] Therefore, hydroxychloroquine sulfate tablets are not recommended in patients taking other drugs that have the potential to prolong the QT interval. Correct electrolyte imbalances prior to use. Monitor cardiac function as clinically indicated during hydroxychloroquine sulfate tablets therapy. Discontinue hydroxychloroquine sulfate tablets if cardiotoxicity is suspected or demonstrated by tissue biopsy.

5.2 Retinal Toxicity Irreversible retinal damage was observed in some patients treated with hydroxychloroquine sulfate and it is related to cumulative dosage and treatment duration. In patients of Asian descent, retinal toxicity may first be noticed outside the macula. Risk factors for retinal damage include daily hydroxychloroquine sulfate dosages ≥5 mg/kg of actual body weight, durations of use greater than five years, renal impairment, use of concomitant drug products such as tamoxifen citrate, and concurrent macular disease. Within the first year of starting hydroxychloroquine sulfate tablets, a baseline ocular examination is recommended including 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). For patients at higher risk of retinal damage, monitoring should include annual examinations which include BCVA, VF and SD-OCT. For patients without significant risk factors, annual retinal exams can usually be deferred until five years of treatment. In patients of Asian descent, it is recommended that visual field testing be performed in the central 24 degrees instead of the central 10 degrees. If ocular toxicity is suspected, discontinue hydroxychloroquine sulfate tablets and monitor the patient closely given that retinal changes and visual disturbances may progress even after cessation of therapy.

5.3 Serious Skin Reactions Serious adverse reactions have been reported with the use of hydroxychloroquine sulfate tablets 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 skin reactions such as blisters on the skin, eyes, lips or in the mouth, itching or burning, with or without fever [ see Warnings and Precautions (5.4 , 5.5 ), Adverse Reactions (6) ] . Discontinue hydroxychloroquine sulfate tablets if these severe reactions occur.

5.4 Worsening of Psoriasis Administration of hydroxychloroquine sulfate tablets to patients with psoriasis may precipitate a severe flare-up of psoriasis. Avoid hydroxychloroquine sulfate tablets in patients with psoriasis, unless the benefit to the patient outweighs the possible risk.

5.5 Risks Associated with Use in Porphyria Administration of hydroxychloroquine sulfate tablets to patients with porphyria may exacerbate porphyria. Avoid hydroxychloroquine sulfate tablets in patients with porphyria.

Hepatotoxicity

Associated with Porphyria Cutanea Tarda Cases of hepatotoxicity have been reported when hydroxychloroquine was used in patients with porphyria cutanea tarda (PCT). Patients received dosages ranging from 200 mg twice weekly to 400 mg daily. Most of the PCT-related cases presented with marked elevations in transaminases (>20 times upper limit of the reference range) within days to a month of hydroxychloroquine initiation. In some cases, PCT was diagnosed only after the occurrence of treatment-induced liver injury, when hydroxychloroquine was prescribed for an approved indication. Some of the cases were associated with other risk factors for hepatic injury (e.g., alcohol use, concomitant hepatotoxic medications). Measure liver tests promptly in patients who report symptoms that may indicate liver injury, such as fatigue, rash, nausea, dark urine, or jaundice. In this clinical context, if the patient is found to have abnormal serum liver tests (e.g., ALT level greater than three times the upper limit of the reference range, total bilirubin greater than two times the upper limit of the reference range), interrupt treatment with hydroxychloroquine sulfate tablets, and investigate further to establish the probable cause. The safety and effectiveness of hydroxychloroquine sulfate tablets for the treatment of PCT have not been established and hydroxychloroquine sulfate tablets is not approved for this use.

5.6 Hematologic Toxicity Hydroxychloroquine sulfate tablets may cause myelosuppression including aplastic anemia, agranulocytosis, leukopenia, or thrombocytopenia. Monitor blood cell counts periodically in patients on prolonged hydroxychloroquine sulfate tablets therapy. If the patient develops myelosuppression which cannot be attributable to the disease, discontinue the drug.

5.7 Hemolytic Anemia Associated with G6PD Deficiency Hemolysis has been reported in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Monitor for hemolytic anemia as this can occur, particularly in association with other drugs that cause hemolysis.

5.8 Skeletal Muscle Myopathy or Neuropathy Skeletal muscle myopathy or 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. <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1 , 5.11) ]</span> Assess muscle strength and deep tendon reflexes periodically in patients on long-term therapy with hydroxychloroquine sulfate tablets. Discontinue hydroxychloroquine sulfate tablets if muscle or nerve toxicity is suspected or demonstrated by tissue biopsy.

5.9 Neuropsychiatric Reactions Including Suicidality Suicidal behavior, suicidal ideation, and other neuropsychiatric adverse reactions have been reported in patients treated with hydroxychloroquine sulfate tablets [ see Adverse Reactions (6) ] . Neuropsychiatric adverse reactions typically occurred within the first month after the start of treatment with hydroxychloroquine and have been reported in patients with and without a prior history of psychiatric disorders. The risks and benefits of continued treatment with hydroxychloroquine sulfate tablets should be assessed for patients who develop these symptoms. Given the long half-life of the drug, some patients may require several weeks off drug for symptoms to partially or fully abate. Advise patients to contact their healthcare provider promptly if they experience new or worsening neuropsychiatric symptoms such as depression, suicidal thoughts or behavior, or mood changes.

5.10 Hypoglycemia Hydroxychloroquine sulfate tablets can cause severe and potentially life-threatening hypoglycemia, in the presence or absence of antidiabetic agents [ see Drug Interactions (7)] . Measure blood glucose in patients presenting with clinical symptoms suggestive of hypoglycemia and as adjust the antidiabetic treatment as necessary. Warn hydroxychloroquine sulfate tablets -treated patients about the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia; diabetic patients should monitor their blood sugar levels. Advise patients to seek medical attention if they develop any signs and symptoms of hypoglycemia.

5.11 Renal toxicity Proteinuria with or without moderate reduction in glomerular filtration rate have been reported with the use of hydroxychloroquine sulfate tablets. Renal biopsy showed phospholipidosis without immune deposits, inflammation, and/or increased cellularity. Physicians should consider phospholipidosis as a possible cause of renal injury in patients with underlying connective tissue disorders who are receiving hydroxychloroquine sulfate tablets. Drug-induced phospholipidosis may occur in other organ systems [ see Warnings and Precautions (5.1 , 5.8 ) ]. Discontinue hydroxychloroquine sulfate tablets if renal toxicity is suspected or demonstrated by tissue biopsy.

PRECAUTIONS General: Use with caution in patients with gastrointestinal, neurological, or blood disorders, and in those with a sensitivity to quinine.

Hepatic/Renal

Disease Antimalarial compounds should be used with caution in patients with hepatic disease or alcoholism or in conjunction with known hepatotoxic drugs. A reduction in dosage may be necessary in patients with hepatic or renal disease, as well as in those taking medicines known to affect these organs.

Hematologic Effects/Laboratory

Tests Antimalarial compounds should be used with caution in patients with hepatic disease or alcoholism or in conjunction with known hepatotoxic drugs. Periodic blood cell counts should be performed if patients are given prolonged therapy. If any severe blood disorder such as aplastic anemia, agranulocytosis, leukopenia, or thrombocytopenia, appears which is not attributable to the disease under treatment, consider discontinuation of hydroxychloroquine sulfate. Hydroxychloroquine sulfate should be administered with caution in patients having glucose-6-phosphate dehydrogenase (G-6-PD) deficiency.

Dermatologic Effects

Dermatologic reactions to hydroxychloroquine sulfate may occur and, therefore, proper care should be exercised when it is administered to any patient receiving a drug with a significant tendency to produce dermatitis.

Drug Interactions

Digoxin: Concomitant hydroxychloroquine sulfate and digoxin therapy may result in increased serum digoxin levels: serum digoxin levels should be closely monitored in patients receiving combined therapy. Insulin or antidiabetic drugs As hydroxychloroquine sulfate may enhance the effects of a hypoglycemic treatment, a decrease in doses of insulin or antidiabetic drugs may be required. Drugs that prolong QT interval and other arrhythmogenic drugs Hydroxychloroquine sulfate prolongs the QT interval and should not be administered with other drugs that have the potential to induce cardiac arrhythmias. Also, there may be an increased risk of inducing ventricular arrhythmias if hydroxychloroquine sulfate is used concomitantly with other arrhythmogenic drugs. Mefloquine and other drugs known to lower the convulsive threshold Hydroxychloroquine sulfate can lower the convulsive threshold. Coadministration of hydroxychloroquine sulfate with other antimalarials known to lower the convulsion threshold (e.g., mefloquine) may increase the risk of convulsions. Antiepileptics: The activity of antiepileptic drugs might be impaired if coadministered with hydroxychloroquine sulfate. Methotrexate: Combined use of methotrexate with hydroxychloroquine sulfate has not been studied and may increase the incidence of adverse effects. Cyclosporin: An increased plasma cyclosporin level was reported when cyclosporin and hydroxychloroquine sulfate were coadministered. The following interactions have been observed on treatment with the structurally related substance chloroquine phosphate, and therefore cannot be ruled out for hydroxychloroquine.

Praziquantel

Chloroquine has been reported to reduce the bioavailability of praziquantel. Antacids and kaolin Antacids and kaolin can reduce absorption of chloroquine; an interval of at least 4 hours between intake of these agents and chloroquine should be observed.

Cimetidine

Cimetidine can inhibit the metabolism of chloroquine, increasing its plasma level. Concomitant use of cimetidine should be avoided. Ampicillin In a study of healthy volunteers, chloroquine significantly reduced the bioavailability of ampicillin. Information for Patients Patients should be informed of the early signs and symptoms of toxicity such as rash or visual changes. Patients must see their physicians promptly in case of the appearance of these or of any unusual effects. Periodic laboratory tests may be recommended in some patients. Patients should be fully informed of the potential risks of the use of hydroxychloroquine sulfate, especially in pregnancy and in children. Carcinogenesis, mutagenesis, impairment of fertility: Long-term studies in animals have not been conducted to evaluate the carcinogenic potential of hydroxychloroquine sulfate. The mutagenic potential of hydroxychloroquine was not evaluated. However, chloroquine has been shown to be a catalytic inhibitor of DNA repair enzymes (topoisomerase II) and to produce weak genotoxic effects through this mode of action.

Pregnancy Teratogenic Effects

Human pregnancies resulting in live births have been reported in the literature and no increase in the rate of birth defects has been demonstrated. Embryonic deaths and malformations of anophthalmia and microphthalmia in the offspring have been reported when pregnant rats received large doses of chloroquine.

Nursing Mothers

Caution should be exercised when administering hydroxychloroquine sulfate to nursing women. It has been demonstrated that hydroxychloroquine administered to nursing women is excreted in human milk and it is known that infants are extremely sensitive to the toxic effects of 4-aminoquinolines.

Pediatric

Use: Safety and efficacy have not been established in the chronic use of hydroxychloroquine sulfate for systemic lupus erythematosus and juvenile idiopathic arthritis in children. Children are especially sensitive to the 4-aminoquinoline compounds. Most reported fatalities followed the accidental ingestion of chloroquine, sometimes in small doses (0.75 g or 1 g in one 3-year-old child). Patients should be strongly warned to keep these drugs out of the reach of children (see OVERDOSAGE ).

Geriatric

Use: Clinical studies of hydroxychloroquine sulfate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. However, this drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function.

INTERACTIONS

• Drugs Prolonging QT Interval and Other Arrhythmogenic Drugs. ( 7.1 )
• See FPI for more important drug interactions. ( 7 )

7.1 Drugs Prolonging QT Interval and Other Arrhythmogenic Drugs Hydroxychloroquine sulfate tablets prolong the QT interval. There may be an increased risk of inducing ventricular arrhythmias if hydroxychloroquine sulfate tablets are used concomitantly with other arrhythmogenic drugs. Therefore, hydroxychloroquine sulfate tablets are not recommended in patients taking other drugs that have the potential to prolong the QT interval or are arrhythmogenic <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 )]</span> .

7.2 Insulin or Other Antidiabetic Drugs Hydroxychloroquine sulfate tablets may enhance the effects of insulin and antidiabetic drugs, and consequently increase the hypoglycemic risk. Therefore, a decrease in dosage of insulin and other antidiabetic drugs may be necessary <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.8 )]</span>.

7.3 Drugs that Lower the Seizure Threshold Hydroxychloroquine sulfate tablets can lower the seizure threshold. Co-administration of hydroxychloroquine sulfate tablets with other antimalarials known to lower the seizure threshold (e.g., mefloquine) may increase the risk of seizures.

7.4 Antiepileptics The activity of antiepileptic drugs might be impaired if co-administered with hydroxychloroquine sulfate tablets.

7.5 Methotrexate Concomitant use of hydroxychloroquine sulfate tablets and methotrexate may increase the incidence of adverse reactions.

7.6 Cyclosporine An increased plasma cyclosporin level was reported when cyclosporine and hydroxychloroquine sulfate tablets were co-administered. Monitor serum cyclosporine levels closely in patients receiving combined therapy.

7.7 Digoxin Concomitant hydroxychloroquine sulfate tablets and digoxin therapy may result in increased serum digoxin levels. Monitor serum digoxin levels closely in patients receiving combined therapy.

7.8 Cimetidine Concomitant use of cimetidine resulted in a 2-fold increase of exposure of chloroquine, which is structurally related to hydroxychloroquine. Interaction of cimetidine with hydroxychloroquine cannot be ruled out. Avoid concomitant use of cimetidine.

7.9 Rifampicin Lack of efficacy of hydroxychloroquine was reported when rifampicin was concomitantly administered. Avoid concomitant use of rifampicin.

7.10 Praziquantel Chloroquine has been reported to reduce the bioavailability of praziquantel. Interaction of praziquantel with hydroxychloroquine cannot be ruled out.

7.11 Antacids and kaolin Antacids and kaolin can reduce absorption of chloroquine; an interval of at least 4 hours between intake of these agents and chloroquine should be observed. Interaction of antacids and kaolin with hydroxychloroquine cannot be ruled out.

7.12 Ampicillin In a study of healthy volunteers, chloroquine significantly reduced the bioavailability of ampicillin. Interaction of ampicillin with hydroxychloroquine cannot be ruled out.