PLAQUENIL (hydroxychloroquine sulfate) is an antimalarial and antirheumatic drug, chemically described as 2-[[4-[(7-Chloro-4- quinolyl) amino]pentyl] ethylamino]ethanol sulfate (1:1) with the molecular formula C 18 H 26 ClN 3 O•H 2 SO 4 . The molecular weight of hydroxychloroquine sulfate is 433.95. Its structural formula is: Hydroxychloroquine sulfate is a white or off-white crystalline powder, freely soluble in water; practically soluble in alcohol, chloroform, and ether. PLAQUENIL (hydroxychloroquine sulfate) tablets for oral administration contain 200 mg hydroxychloroquine sulfate (equivalent to 155 mg of hydroxychloroquine) and the following inactive ingredients: black iron oxide, carnauba wax, corn starch, dibasic calcium phosphate, hydroxypropyl methylcellulose, magnesium stearate, polyethylene glycol 400, polysorbate 80, titanium dioxide. chem-formula

PLAQUENIL is 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. • Prophylaxis of malaria in geographic areas where chloroquine resistance is not reported in adult and pediatric patients. • Treatment of rheumatoid arthritis in adults. • Treatment of systemic lupus erythematosus in adults. • Treatment of chronic discoid lupus erythematosus in adults. Limitations of Use: PLAQUENIL is 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

Malaria PLAQUENIL is 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: PLAQUENIL is not recommended for: • Treatment of complicated malaria. • Treatment of malaria by 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 . For the most current information about drug resistance, refer to the latest recommendations from the Center for Disease Control and Prevention 1

Rheumatoid Arthritis PLAQUENIL is indicated for the treatment of acute and chronic rheumatoid arthritis in adults

Systemic Lupus Erythematosus PLAQUENIL is indicated for the treatment of systemic lupus erythematosus in adults

Chronic Discoid Lupus Erythematosus PLAQUENIL is indicated for the treatment of chronic discoid lupus erythematosus in adults.

Tablets: 200 mg of hydroxychloroquine sulfate, white to off-white, film-coated tablet imprinted with “PLAQUENIL” on one face in black ink. Tablets: 200 mg of hydroxychloroquine sulfate

Malaria in Adult and Pediatric Patients : 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 : 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: 200 mg once daily or 400 mg once daily (or in two divided doses) Chronic Discoid Lupus Erythematosus in Adults: 200 mg once daily or 400 mg once daily (or in two divided doses) 2.1 Important Administration Instructions Administer PLAQUENIL orally with food or milk. Do not crush or divide the tablets

Dosage for Malaria in Adult and Pediatric Patients PLAQUENIL is 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 = 2000 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 2000 mg). For radical cure of P. vivax and P. ovale infections, concomitant therapy with an 8-aminoquinoline drug is necessary

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 . • 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 PLAQUENIL

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

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.

• Cardiomyopathy and Ventricular Arrhythmias : Fatal or life-threatening cardiomyopathy and ventricular arrhythmias were reported. • Retinal Toxicity : Irreversible retinal damage is related to cumulative dosage and treatment duration. Baseline retinal exam and exams during treatment are recommended. • Serious Skin Reactions : Stevens Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, acute generalized exanthematous pustulosis have been reported. • Worsening of Psoriasis : Avoid in patients with psoriasis. • Risks Associated with Use in Porphyria : Avoid in patients with porphyria. Hepatotoxicity was reported in patients with porphyria cutanea tarda. • Hematologic Toxicity: Discontinue if myelosuppression occurs. • Renal Toxicity: Consider phospholipidosis as a possible cause of renal injury in patients with underlying connective tissue disorders. Discontinue PLAQUENIL 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 PLAQUENIL. Signs and symptoms of cardiac compromise have occurred during acute and chronic PLAQUENIL 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 . 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. PLAQUENIL has a potential to prolong the QT interval. Ventricular arrhythmias (including torsades de pointes) have been reported in PLAQUENIL-treated patients. The magnitude of QT prolongation may increase with increasing concentrations of the drug. Therefore, the recommended dose should not be exceeded . Avoid PLAQUENIL 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 agents as this may lead to an increased risk for ventricular arrhythmias . Therefore, PLAQUENIL is 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 PLAQUENIL therapy. Discontinue PLAQUENIL if cardiotoxicity is suspected or demonstrated by tissue biopsy

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 PLAQUENIL, 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 PLAQUENIL and monitor the patient closely given that retinal changes and visual disturbances may progress even after cessation of therapy

Serious Skin Reactions Serious adverse reactions have been reported with the use of PLAQUENIL 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 . Discontinue PLAQUENIL if these severe reactions occur

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

Risks Associated with Use in Porphyria Administration of PLAQUENIL to patients with porphyria may exacerbate porphyria. Avoid PLAQUENIL 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 PLAQUENIL, and investigate further to establish the probable cause. The safety and effectiveness of PLAQUENIL for the treatment of PCT have not been established and PLAQUENIL is not approved for this use

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

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

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 . Assess muscle strength and deep tendon reflexes periodically in patients on long-term therapy with PLAQUENIL. Discontinue PLAQUENIL if muscle or nerve toxicity is suspected or demonstrated by tissue biopsy

Neuropsychiatric Reactions Including Suicidality Suicidal behavior, suicidal ideation, and other neuropsychiatric adverse reactions have been reported in patients treated with PLAQUENIL . 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 PLAQUENIL 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

Hypoglycemia PLAQUENIL can cause severe and potentially life-threatening hypoglycemia, in the presence or absence of antidiabetic agents . Measure blood glucose in patients presenting with clinical symptoms suggestive of hypoglycemia and as adjust the antidiabetic treatment as necessary. Warn PLAQUENIL-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

Renal Toxicity Proteinuria with or without moderate reduction in glomerular filtration rate have been reported with the use of PLAQUENIL. 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 PLAQUENIL. Drug-induced phospholipidosis may occur in other organ systems . Discontinue PLAQUENIL if renal toxicity is suspected or demonstrated by tissue biopsy.

• Drugs Prolonging QT Interval and Other Arrhythmogenic Drugs. • See FPI for more important drug interactions.( 7 ) 7.1 Drugs Prolonging QT Interval and Other Arrhythmogenic Drugs PLAQUENIL prolongs the QT interval. There may be an increased risk of inducing ventricular arrhythmias if PLAQUENIL is used concomitantly with other arrhythmogenic drugs. Therefore, PLAQUENIL is not recommended in patients taking other drugs that have the potential to prolong the QT interval or are arrhythmogenic

Insulin or Other Antidiabetic Drugs PLAQUENIL 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

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

Antiepileptics The activity of antiepileptic drugs might be impaired if co-administered with PLAQUENIL

Methotrexate Concomitant use of PLAQUENIL and methotrexate may increase the incidence of adverse reactions

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

Digoxin Concomitant PLAQUENIL and digoxin therapy may result in increased serum digoxin levels. Monitor serum digoxin levels closely in patients receiving combined therapy

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

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

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

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